Cochrane Review: Zinc for the common cold

Authors


Abstract

Background

The common cold is one of the most widespread illnesses and is a leading cause of visits to the doctor and absenteeism from school and work. Trials conducted since 1984 investigating the role of zinc for the common cold symptoms have had mixed results. Inadequate treatment masking and reduced bioavailability of zinc from some formulations have been cited as influencing results.

Objectives

To assess the effect of zinc on common cold symptoms.

Search methods

We searched CENTRAL (2010, Issue 2) which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to May week 3, 2010) and EMBASE (1974 to June 2010).

Selection criteria

Randomised, double-blind, placebo-controlled trials using zinc for at least five consecutive days to treat, or for at least five months to prevent the common cold.

Data collection and analysis

Two review authors independently extracted data and assessed trial quality.

Main results

We included 13 therapeutic trials (966 participants) and two preventive trials (394 participants). Intake of zinc is associated with a significant reduction in the duration (standardised mean difference (SMD) -0.97; 95% confidence interval (CI) -1.56 to -0.38) (P = 0.001), and severity of common cold symptoms (SMD -0.39; 95% CI -0.77 to -0.02) (P = 0.04). There was a significant difference between the zinc and control group for the proportion of participants symptomatic after seven days of treatment (OR 0.45; 95% CI 0.2 to 1.00) (P = 0.05). The incidence rate ratio (IRR) of developing a cold (IRR 0.64; 95% CI 0.47 to 0.88) (P = 0.006), school absence (P = 0.0003) and prescription of antibiotics (P < 0.00001) was lower in the zinc group. Overall adverse events (OR 1.59; 95% CI 0.97 to 2.58) (P = 0.06), bad taste (OR 2.64; 95% CI 1.91 to 3.64) (P < 0.00001) and nausea (OR 2.15; 95% CI 1.44 to 3.23) (P = 0.002) were higher in the zinc group.

Authors' conclusions

Zinc administered within 24 hours of onset of symptoms reduces the duration and severity of the common cold in healthy people. When supplemented for at least five months, it reduces cold incidence, school absenteeism and prescription of antibiotics in children. There is potential for zinc lozenges to produce side effects. In view of this and the differences in study populations, dosages, formulations and duration of treatment, it is difficult to make firm recommendations about the dose, formulation and duration that should be used.

Plain Language Summary

Zinc for the common cold

The common cold is often caused by the rhinovirus. It is one of the most widespread illnesses and is a leading cause of visits to the doctor and absenteeism from school and work. Complications of the common cold include otitis media (middle ear infection), sinusitis and exacerbations of reactive airway diseases. There is no proven treatment for the common cold. However, a medication that is even partially effective in the treatment and prevention of the common cold could markedly reduce morbidity and economic losses due to this illness.

Zinc inhibits rhinoviral replication and has been tested in trials for treatment of the common cold. This review identified 15 randomized controlled trials, enrolling 1360 participants of all age groups, comparing zinc with placebo (no zinc). We found that zinc (lozenges or syrup) is beneficial in reducing the duration and severity of the common cold in healthy people, when taken within 24 hours of onset of symptoms. People taking zinc are also less likely to have persistence of their cold symptoms beyond seven days of treatment. Zinc supplementation for at least five months reduces incidence, school absenteeism and prescription of antibiotics for children with the common cold. People taking zinc lozenges (not syrup or tablet form) are more likely to experience adverse events, including bad taste and nausea. As there are no studies in participants in whom common cold symptoms might be troublesome (for example, those with underlying chronic illness, immunodeficiency, asthma, etc.), the use of zinc currently cannot be recommended for them. Given the variability in the populations studied (no studies from low- or middle-income countries), dose, formulation and duration of zinc used in the included studies, more research is needed to address these variabilities and determine the optimal duration of treatment as well as the dosage and formulations of zinc that will produce clinical benefits without increasing adverse effects, before making a general recommendation for zinc in treatment of the common cold.

Summary of findings for the main comparison [Explanation]

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Background

Description of the condition

The common cold is one of the most widespread illnesses, with adults having two to four episodes annually (Garibaldi 1985). Children may have six to 10 colds a year (and up to 12 colds a year for school children) (Simasek 2007). In the United States, the common cold leads to 75 to 100 million physician visits annually at a conservative cost estimate of US $7.7 billion per year. Americans spend $2.9 billion on over-the-counter drugs and another $400 million on prescription medicines for symptomatic relief (Garibaldi 1985; Simasek 2007). More than one-third of patients who saw a doctor received an antibiotic prescription, which has implications for antibiotic resistance from overuse of such drugs (Fendrick 2003). An estimated 22 to 189 million school days are missed annually due to a cold. As a result, parents missed 126 million workdays to stay home to care for their children. When added to the 150 million work days missed by employees suffering from a cold, the total economic impact of cold-related work loss exceeds $20 billion per year (Fendrick 2003; Garibaldi 1985). This accounts for 40% of time lost from work (Kirkpatrick 1996). The complications of the common cold include otitis media, sinusitis and exacerbations of reactive airway diseases (Couch 1984; Gwaltney 1966; Turner 2001). Rhinoviruses are the most frequent cause and may account for nearly 80% of common colds during autumn (Turner 2001). There is no proven treatment for the common cold. However, even a medication that is only partially effective in the treatment and prevention of the common cold could markedly reduce morbidity and economic losses due to this illness.

Description of the intervention

The effect of zinc lozenges on the incidence, duration or severity of common cold symptoms has been examined in different studies since 1984. In 1984, Eby et al (Eby 1984) reported for the first time on the efficacy of zinc gluconate lozenges for treatment of the common cold. However, later trials have given variable results. It has been hypothesized that there is a direct correlation between reductions in the duration of common cold symptoms and the daily dosage of all positively charged zinc species released from lozenges at physiologic pH (Eby 1995). The re-analysis of 10 double-blind, placebo-controlled zinc trials by solution chemistry methods showed a significant correlation between total daily dosages of positively charged zinc species and a reduction in the mean duration of common colds (Eby 2004). Zinc gluconate and zinc acetate have very low chemical stability and mainly release positively charged zinc ions in aqueous solutions at physiologic pH, but stronger complexes do not (Eby 2004). Adding a strong zinc binding ligand, such as glycine or citric acid, to a solution containing a zinc complex that is weakly bonded results in the sequestration of zinc to the stronger ligand, reducing or eliminating the benefits of zinc lozenges (Eby 2004). In the review by Marshall it was concluded that zinc gluconate lozenges were effective in reducing the symptoms and duration of the common cold but the side effects and particularly bad taste might limit patient compliance (Marshall 1998). However, results from three trials (Kurugol 2006a; Kurugol 2006b; Kurugol 2007) using zinc sulfate syrup and one trial using zinc sulfate tablet (Vakili 2009) suggested that both the syrup and tablet form are well tolerated and an easy to administer therapy. Adverse effects were mild and had no significant association with the use of zinc sulfate syrup or tablet. The increased incidence of adverse effects noted in the zinc group in various trials may have been related to the use of different ligands (gluconate, acetate) rather than to zinc itself.

How the intervention might work

Interest in the use of zinc for the common cold grew following the results of a randomized controlled trial (RCT) conducted by Eby 1984. Results suggested that if treatment of a cold commenced within three days of the development of cold symptoms and consisted of one 23 mg zinc lozenge dissolved in the mouth every second waking hour, the average duration of cold symptoms was reduced by about seven days. This result was consistent with the earlier observation by Eby (Eby 1984) that a three-year old girl diagnosed with acute lymphocytic leukaemia who had been treated with a 50 mg zinc tablet to improve her zinc status and to stimulate T-cell lymphocyte responsiveness recovered from a cold within several hours of receiving treatment. In addition, this effect was claimed to be reproducible in other children and adults. Later trials gave inconclusive results (Turner 2001). Results of trials in which no effect of zinc was demonstrated were criticised for having inadequate sample sizes or formulations that reduced the release of zinc ions from the lozenge (Eby 1995).

In-vitro assays indicate that zinc possesses antiviral properties (concentrations of 0.1 mM zinc inhibited growth of eight of nine strains of rhinoviruses) and although such activity suggests Eby's results are biologically plausible, only a handful of RCTs have been able to duplicate his findings. Of the 18 trials conducted since 1984, 11 trials have shown zinc may be useful in the treatment of the common cold and seven have shown no benefit. Most trials showing beneficial effects have been criticised for failing to mask treatment adequately due to the occurrence of side effects, while trials showing no benefit have been criticised for using formulations that reduced the bioavailability of zinc.

Although several possibilities have been suggested, the mechanisms of the efficacy of zinc on the common cold are still unexplained. One possibility is that the interaction of zinc with host immune function may have a beneficial effect on common cold symptoms (Macknin 1999). Human rhinoviruses, attaching to the nasal epithelium via the intracellular adhesion molecule-1 (ICAM-1) receptor, cause most colds. The zinc ion, based on its electrical charge, has an affinity for ICAM-1 receptor sites and may exert an antiviral effect by attaching to the ICAM-1 receptors in the rhinovirus structure and nasal epithelial cells (Novick 1996). In addition, zinc inhibits viral replication by preventing the formation of viral capsid proteins (Geist 1987; Korant 1976). It has also been suggested that zinc stabilises cell membranes (Pasternak 1987), prevents histamine release (Harisch 1987) and inhibits prostaglandin metabolism (Kelly 1983).

Why it is important to do this review

There is no proven method of prevention or treatment for the common cold. However, any medication that is only partially effective in the treatment and prevention of the common cold could markedly reduce morbidity and economic losses due to this illness. There have been many clinical trials describing the effect of zinc (lozenges and syrup) on common cold symptoms; therefore it is important to know the effect of zinc on the common cold. The last review of all available RCTs of zinc for the common cold was published in 1999. Since then, several new studies (Kurugol 2006a; Kurugol 2006b; Kurugol 2007; Macknin 1998; McElroy 2003; Petrus 1998; Prasad 2000; Prasad 2008; Turner 2000; Vakili 2009; Veverka 2009) have been published. It is therefore important to update the information by including all the new clinical trials. We therefore undertook the review to assess the overall effectiveness of zinc (lozenges or syrup) in treating the common cold and to provide some guidance with respect to future research.

Objectives

The objective of the review was to investigate whether zinc (irrespective of the zinc salt or formulation used) is efficacious in reducing the incidence, severity and duration of common cold symptoms. In addition, we aimed to identify potential sources of heterogeneity in results obtained and to assess their clinical significance.

Methods

Criteria for considering studies for this review

Types of studies

Double-blind, placebo-controlled randomized controlled trials (RCTs).

Types of participants

Trial participants were of either gender and of any age.

Types of interventions

Therapeutic trials: interventions commenced within three days of participants developing common cold symptoms and consisted of 1.5 to 2-hourly treatments with a zinc or placebo lozenge during waking hours, for more than six hours a day for a period of five or more consecutive days.

Prophylactic trials: intervention commenced and continued throughout the cold season for at least five months.

We considered all formulations of zinc (irrespective of the type of salt, formulation and concentration of zinc).

Types of outcome measures

Outcome measures frequently used to determine the clinical efficacy of any common cold treatment are the incidence, severity and duration of cold symptoms. Accordingly, for inclusion in this review, the incidence and severity of at least throat and nasal symptoms and cough needed to be assessed.

Primary outcomes
  • 1.Duration of symptoms.
  • 2.Severity of symptoms.
  • 3.Incidence of the common cold.
Secondary outcomes
  • 1.Proportion of participants symptomatic after three, five or seven days of treatment.
  • 2.Time to resolution of individual symptoms: cough, nasal congestion, nasal drainage and sore throat.
  • 3.Change in individual severity symptom scores: cough, nasal score.
  • 4.School absence (days).
  • 5.Antibiotic use.
  • 6.Adverse events.

We defined duration as the number of days to cold resolution from start of treatment. We considered cold resolution to be the resolution of all cold symptoms or resolution of all but one cold symptom, or the participant believed they had recovered from the cold. Severity of cold symptoms needed to be graded: 0 - no symptoms, 1 - mild symptoms, 2 - moderate symptoms and 3 - severe symptoms. We defined incidence as number of colds per study participant during the study period. Adverse events included any or individual adverse events during or after taking the medications.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 2) which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to May week 3, 2010) and EMBASE (1974 to June 2010). We combined the MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity- and precision-maximising version (2009 revision); Ovid format (Lefebvre 2009). See Appendix 1 for the EMBASE search strategy.

MEDLINE (OVID)

1     Common Cold/

2     common cold*.tw.

3     Rhinovirus/

4     rhinovir*.tw.

5     Rhinitis/

6     rhinit*.tw.

7     coryza.tw.

8     (respiratory infection* adj3 upper).tw.

9     (infection* adj3 upper respiratory).tw.

10     (urti or uri).tw.

11     or/1-10

12     Zinc/

13     (zinc or zn).tw.

14     Micronutrients/

15     micronutrient*.tw.

16     Trace Elements/

17     (trace adj (mineral* or element*)).tw.

18     or/12-17

19     11 and 18

Searching other resources

We searched bibliographies of published papers for unpublished trials. Two review authors (RRD, MS) assessed the studies to ensure appropriate trials were included in the review and to minimise the potential for selection bias.

Data collection and analysis

More information on the statistical methods used in this review can be found in the relevant section of the Cochrane Acute Respiratory Infections Review Group Module. Comparisons were zinc (lozenges or syrup or tablet) with placebo. We compared outcome measures before and after treatment, as well as after day three, five or seven to accommodate trials of different lengths.

Selection of studies

Two review authors (RRD, MS) independently reviewed the results for inclusion in the analysis. We resolved differences regarding study quality through discussion.

Data extraction and management

We recorded data on a pre-structured data extraction form. The lead review author (MS) entered data directly into Review Manager (RevMan) (RevMan 2008). An independent coder verified accuracy of data entry. We made no attempt to contact investigators. Most trials were conducted over 10 years ago and in view of the information required to be provided by the investigators, we thought that they would be unable to comply.

Assessment of risk of bias in included studies

We assessed risk of bias in all included studies using the Cochrane Collaboration's 'Risk of bias' tool (Higgins 2009).

1. Sequence generation: assessed as yes, no or unclear

Yes: when the study described the method used to generate the allocation sequence in sufficient detail.

No: sequence not generated.

Unclear: when it was not described or incompletely described.

2. Allocation concealment: assessed as yes, no or unclear

Yes: when the study described the method used to conceal the allocation sequence in sufficient detail.

No: described details where allocation concealment was not done.

Unclear: when it was not described or incompletely described.

3. Blinding of participants, personnel and outcome assessors: assessed as yes, no or unclear

Yes: when it was a double-blind study.

No: when it was an unblinded study.

Unclear: not clearly described.

4. Incomplete outcome data: assessed as yes, unclear

Yes: describe the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis.

Unclear: either not described or incompletely described.

5. Free of selective outcome reporting: assessed as yes, no or unclear

Yes: results of study free of selective reporting. Details of all the patients enrolled in the study are included in the paper.

No: details of all the enrolled patients not given in the paper.

Unclear: details of all the enrolled patients incompletely described.

6. Other sources of bias

Among the other sources of potential bias considered was funding agencies and their role in the study. We recorded funding agencies as government agencies, universities and research organisations or pharmaceutical companies. We considered studies supported by pharmaceutical companies to be unclear unless the study defined the role of the pharmaceutical companies. We also considered studies not mentioning the source of funding as unclear under this heading.

Trials were assessed with respect to the extent to which investigators minimised the potential for bias to occur and addressed other issues in relation to methodological quality. Two review authors (RRD, MS) assessed the quality of each trial. When the methodological description was unambiguous, one review author entered the methodological description to the ‘Risk of bias’ tables in Characteristics of included studies tables. When the description of methods was ambiguous, the same review author discussed the issue with the co-author to reach a consensus. Themethodological descriptions are summarised in Figure 1 and Figure 2.

Figure 1.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Figure 2.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

We assessed the potential for selection (systematic differences in the comparison groups), performance (systematic difference in the care provided apart from the intervention being evaluated), exclusion (systematic differences in withdrawals from the trial) and detection (systematic differences in outcome assessment) bias.

Given that the extent to which trial investigators addressed each criterion could influence the potential for bias to occur, and the extent to which the resulting bias could influence the results is not known, we considered the potential for each criterion to bias the results of a trial equal to the other criterion used.

Measures of treatment effect

We extracted outcome data and entered data into RevMan 5 for statistical analysis. We used the standard methods of the Cochrane Acute Respiratory Infections (ARI) Review Group to synthesise the data. For dichotomous data, we calculated a pooled estimate of the treatment effect for each outcome across trials using the odds ratio (OR). For continuous outcomes, we recorded both mean post-treatment or post-intervention values and standard deviation (SD). If standard errors (SE) had been reported (and if it were possible) we planned to convert these to standard deviations. We calculated a pooled estimate of treatment effect by calculating the standardised mean difference (SMD). For both dichotomous and continuous outcomes, we calculated the 95% confidence interval (95% CI) for individual studies. We used fixed-effect models to obtain summary statistics of all types of outcome measures. When significant heterogeneity was found, we calculated the overall efficacy using random-effects models, which provided more realistic estimates of the CIs under these circumstances (Lau 1997). In this context, a P value < 0.05 indicated significant differences between studies and raised questions as to whether the results could be meaningfully combined. Where it was not possible to perform a meta-analysis, we summarised the data for each trial.

Unit of analysis issues

Only randomized, double-blind, placebo-controlled trials were included in this review. None of the trials were cross-over or cluster-randomised trials.

Dealing with missing data

As many trials were conducted 10 years ago, we thought that the investigators would be unable to compile the missing data, so we did not contact them. For all the outcomes, we considered that incomplete outcome data had been adequately addressed if 85% or more of the participants were included in the analysis, or if less than 85% were included but adequate steps were taken to ensure or demonstrate that this did not bias the results. We performed intention-to-treat (ITT) analysis where the above was not clear. In trials with missing statistics (such as SDs or correlation coefficients), we calculated the data from the available information.

Assessment of heterogeneity

We assessed the degree of heterogeneity by using the Chi2 test and the I2 statistic (Higgins 2003; Higgins 2009). The Chi2 test is known to be poor at detecting true heterogeneity among studies; while a statistically significant result indicates heterogeneity, a non-significant result is not evidence of no heterogeneity. The I2 statistic describes the percentage of total variation across studies that is due to heterogeneity rather than chance. The values of the I2 statistic lie between 0% and 100%. For the current meta-analysis, we used a simplified categorisation of the I2 statistic as follows: if significant heterogeneity (I2 statistic > 50%) was found, we used a random-effects model and if low heterogeneity (I2 statistic < 50%) was found, we used a fixed-effect model.

Assessment of reporting biases

We sought further information from trial authors, although this was not possible for the current meta-analysis as many of the studies were very old. We looked hard for evidence of collection by study investigators of a small number of key outcomes that are routinely measured in the area in question, and reported which studies reported data on these and which do not. We also constructed a matrix indicating which outcomes were recorded in which studies (for example, with rows as studies and columns as outcomes). Complete and incomplete reporting was also indicated. This matrix showed us which studies did not report outcomes reported by most other studies.  We assessed risk of bias due to selective reporting of outcomes for the study as a whole, rather than for each outcome. We also assessed the likelihood of small study effects, such as publication bias, by examining the funnel plot for asymmetry (Egger 1997).

Data synthesis

We analyzed data using a fixed-effect model in cases of low heterogeneity (I2 statistic value of < 50%) and a random-effects model in cases of moderate to high heterogeneity between studies (I2 statistic value of > 50%).

Subgroup analysis and investigation of heterogeneity

The factors considered as possible explanations for the heterogeneity observed across the results of these studies were: dosage and formulations of zinc used, age of participants (children and adults) and the mean duration of symptoms prior to administration of zinc. We plan to investigate these with subgroup analyses when there are sufficient studies included in the review.

Sensitivity analysis

We had planned to perform sensitivity analyses based on methodological quality of the trials with and without quasi-randomised trials, but this was not possible.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Results of the search

Two review authors (RRD, MS) screened the search results. Prior to 1999, 87 search results resulted in seven included trials in the earlier version of this review (Marshall 1999). After 1999, a total of 57 search results were obtained after removing duplicates (MEDLINE = 37, CENTRAL = 19 and EMBASE = 41 search results). Fifteen trials are included in the review (eight trials were included in this updated review), including 996 participants in the therapeutic trials and 394 in the preventive trials. No trials were found through contact with pharmaceutical companies.

Included studies

We identified 15 trials for inclusion.

Location

Three trials were conducted in Turkey (Kurugol 2006a; Kurugol 2006b; Kurugol 2007); one trial each in Iran (Vakili 2009), Denmark (Weismann 1990), UK (Al-Nakib 1987) and Australia (Douglas 1987); and eight trials in the USA (Farr 1987a; Godfrey 1992; Macknin 1998; Mossad 1996; Petrus 1998; Prasad 2000; Prasad 2008; Smith 1989).

Participants

All the trial participants included in the analysis were both adults and children with age range varying from one to 65 years at the start of the trials. Five trials included children only and among these, three trials included children aged one to 10 years (Kurugol 2006a; Kurugol 2006b; Kurugol 2007); one included children and adolescents aged six to 16 years (Macknin 1998); and another included children aged 6.5 to 10 years (Vakili 2009). Two trials recruited participants from volunteers experimentally inoculated with human rhinovirus (Al-Nakib 1987; Farr 1987a). Given that not all participants had cold symptoms at the beginning of the intervention in one trial (Farr 1987a), this trial would be excluded from the statistical overview. In one trial neither the health status of the participants nor the exclusion criteria were stated, while in other trials only healthy subjects from the general population were included. In one trial, participants with cold durations of more than 24 hours (Macknin 1998) and in another trial participants with cold durations of more than 48 hours (Kurugol 2007) were excluded. The trials varied widely in size; two trials had fewer than 50 participants (Prasad 2000; Prasad 2008), four had more than 50 but fewer than 100 participants (Douglas 1987; Farr 1987a; Godfrey 1992; Mossad 1996), eight had more than 100 but fewer than 200 participants (Al-Nakib 1987; Kurugol 2006a; Kurugol 2006b; Kurugol 2007; Petrus 1998; Smith 1989; Weismann 1990; Vakili 2009) and the largest trial had 247 participants (Macknin 1998).

Interventions

Zinc supplements were provided in the form of either syrup, lozenges or tablets. One trial used zinc sulfate tablet (Vakili 2009) and three trials used zinc sulphate syrup (Kurugol 2006a; Kurugol 2006b; Kurugol 2007). Among the trials using lozenge preparations, two different salts were used: zinc gluconate (Al-Nakib 1987; Farr 1987a; Godfrey 1992; Macknin 1998; Mossad 1996; Smith 1989; Weismann 1990) and zinc acetate (Douglas 1987; Petrus 1998; Prasad 2000; Prasad 2008). The supplements were given for different periods of time in all the trials. In the therapeutic trials the duration of supplement was five days (Farr 1987a), six days (Al-Nakib 1987; Douglas 1987), seven days (Farr 1987a; Godfrey 1992; Smith 1989), 10 days (Kurugol 2006a; Kurugol 2007; Weismann 1990), 14 days (Petrus 1998) and no duration mentioned (i.e. participants were given zinc as long as they were symptomatic) (Macknin 1998; Mossad 1996; Prasad 2000; Prasad 2008). In the three trials also studying the prophylactic role of zinc, the duration of supplement was 4.5 days (Al-Nakib 1987), five months (Vakili 2009) and seven months (Kurugol 2006b).

Outcomes
Primary

Ten trials (Godfrey 1992; Kurugol 2006a; Kurugol 2007; Macknin 1998; Mossad 1996; Petrus 1998; Prasad 2000; Prasad 2008; Smith 1989; Weismann 1990) reported the duration of symptoms, and the results could be pooled from all the trials except four (Godfrey 1992; Mossad 1996; Smith 1989; Weismann 1990), due to different formats of reporting results. Ten trials measured the total severity score of cold symptoms (Al-Nakib 1987; Douglas 1987; Godfrey 1992; Kurugol 2006a; Kurugol 2007; Petrus 1998; Prasad 2000; Prasad 2008; Smith 1989; Weismann 1990) but results from only five trials (Kurugol 2006a; Kurugol 2007; Petrus 1998; Prasad 2000; Prasad 2008) could be pooled, as in five trials (Al-Nakib 1987; Douglas 1987; Godfrey 1992; Smith 1989; Weismann 1990) the results were not reported in a standard format. The incidence of cold symptoms was measured in two trials (Kurugol 2006b; Vakili 2009).

Secondary

The proportion of participants asymptomatic by day three or day five was reported in three trials (Mossad 1996; Smith 1989; Weismann 1990), whereas the proportion of participants asymptomatic by day seven was reported in five trials (Douglas 1987; Godfrey 1992; Mossad 1996; Smith 1989; Weismann 1990). In all these trials, ITT analysis was conducted. Time to resolution of individual cold symptoms was reported as follows: time to resolution of cough in four trials (Kurugol 2006a; Macknin 1998; Prasad 2000; Prasad 2008), time to resolution of nasal congestion in five trials (Kurugol 2006a; Macknin 1998; Petrus 1998; Prasad 2000; Prasad 2008), time to resolution of nasal drainage in five trials (Kurugol 2006a; Macknin 1998; Petrus 1998; Prasad 2000; Prasad 2008) and time to resolution of sore throat in four trials (Kurugol 2006a; Macknin 1998; Prasad 2000; Prasad 2008). Change in individual severity symptom score was reported as follows: change in cough symptom score in two trials (Douglas 1987; Petrus 1998), change in nasal symptom score in four trials (Douglas 1987; Kurugol 2006a; Kurugol 2007; Petrus 1998), change in throat symptom score in two trials (Douglas 1987; Petrus 1998). Standard error of mean (SEM) was not provided in one trial (Douglas 1987). Effect on school absence and antibiotic use were provided in two trials (Kurugol 2006b; Vakili 2009).

Adverse events

Eleven trials (Douglas 1987; Kurugol 2006a; Kurugol 2006b; Kurugol 2007; Macknin 1998; Mossad 1996; Prasad 2000; Prasad 2008; Smith 1989; Weismann 1990; Vakili 2009) reported adverse events. Common adverse events included bad taste, nausea, constipation, diarrhea, abdominal pain, dry mouth and oral irritation.

Other

Two trials using experimentally-induced colds with rhinovirus also studied the number of participants shedding the virus, duration of viral shedding, number of virus-positive days, as well as rise in antibody titre. These were not included in the outcome measures as we thought that it would not be of help in drawing conclusions. Three trials reported the effect of zinc supplementation on school absenteeism. Among these, two (Kurugol 2006b; Vakili 2009) reported this outcome during a prophylactic trial, though another (Macknin 1998) was a therapeutic trial.

Excluded studies

We excluded four trials.

  • 1.Inclusion criteria not defined, disproportionate number of drop outs from the zinc group (Eby 1984).
  • 2.Two studies were not RCTs (McElroy 2003; Turner 2000).
  • 3.Measured upper respiratory tract infection as a whole (including common cold, seasonal influenza) (Veverka 2009).

Risk of bias in included studies

Allocation

Allocation concealment was adequate in 10 studies (Douglas 1987; Farr 1987a; Godfrey 1992; Kurugol 2006a; Kurugol 2006b; Kurugol 2007; Macknin 1998; Mossad 1996; Prasad 2000; Prasad 2008). It was unclear in four studies (Al-Nakib 1987; Petrus 1998; Smith 1989; Weismann 1990) and not described in one (Vakili 2009).

Adequate sequence generation was described in seven studies (Douglas 1987; Godfrey 1992; Kurugol 2006a; Kurugol 2006b; Kurugol 2007; Macknin 1998; Mossad 1996). However, it was not clear in four studies (Farr 1987a; Prasad 2000; Prasad 2008; Smith 1989) and not generated in four studies (Al-Nakib 1987; Petrus 1998; Vakili 2009; Weismann 1990).

Blinding

All 15 studies were blinded but placebo blinding was adequately described in ten trials (Douglas 1987; Smith 1989; Godfrey 1992; Macknin 1998; Mossad 1996; Prasad 2000; Kurugol 2006a; Kurugol 2006b; Kurugol 2007; Prasad 2008). Zinc-treated participants also experienced higher incidences of side effects and/or complaints, and in nine trials, zinc-treated participants complained of altered, bad or unpalatable taste which suggests that the zinc lozenges were distinct from the placebo lozenges and, in this respect, blinding may have been compromised.

Incomplete outcome data

Data were fully detailed in 14 studies and in the remaining one study (Al-Nakib 1987) details of attrition and exclusions from the analysis were unavailable.

Selective reporting

Except two studies (Al-Nakib 1987; Weismann 1990), 13 studies scored 'yes' for being free from selective reporting.

Other potential sources of bias

Eleven studies were funded by pharmaceutical companies (Al-Nakib 1987; Douglas 1987; Godfrey 1992; Farr 1987a; Kurugol 2006a; Kurugol 2006b; Kurugol 2007; Macknin 1998; Petrus 1998; Smith 1989; Weismann 1990). Five studies were supported Medical Research Foundation (Godfrey 1992; Mossad 1996; Prasad 2000; Prasad 2008; Vakili 2009) and in addition by National Institute of Health (NIH) (Prasad 2008). Information on clearance by Ethics Committees or Institutional Review Boards was available for all except one study (Smith 1989).

Effects of interventions

See: Summary of findings for the main comparison

1. Primary outcomes

Duration of cold symptoms

Ten studies (Godfrey 1992; Kurugol 2006a; Kurugol 2007; Macknin 1998; Mossad 1996; Petrus 1998; Prasad 2000; Prasad 2008; Smith 1989; Weismann 1990) reported this outcome. Results could be pooled from all except four studies (Godfrey 1992; Mossad 1996; Smith 1989; Weismann 1990) and there were 762 participants including children and adults (Analysis 1.1; Figure 3). The studies were heterogenous in terms of variable formulations (zinc gluconate or acetate lozenges, zinc sulphate syrup) and dose range (30 to 160 mg/day) as well as mean duration of symptoms prior to administration of zinc (varying from 24 to 48 hours). However, subgroup analysis was not possible as there were not enough studies for each variable. Intake of zinc lozenges or syrup was associated with a significant reduction in the duration of common cold symptoms (SMD −0.97; 95% CI −1.56 to −0.38) (P = 0.001), when it was administered within 24 hours of the onset of symptoms. In one study (Godfrey 1992) the authors found a significant decrease in the duration of symptoms when treatment was administered within 24 hours, compared to treatment administration within 48 hours.

Figure 3.

Forest plot of comparison: 1 Primary outcomes, outcome: 1.1 Duration of cold symptoms (in days).

Severity of cold symptoms

Ten studies measured the mean severity score of cold symptoms (Al-Nakib 1987; Douglas 1987; Godfrey 1992; Kurugol 2006a; Kurugol 2007; Petrus 1998; Prasad 2000; Prasad 2008; Smith 1989; Weismann 1990). Results fromfive studies (Kurugol 2006a; Kurugol 2007; Petrus 1998; Prasad 2000; Prasad 2008) including a total of 513 participants (Analysis 1.2; Figure 4) could be pooled. There was a significant difference between the intervention and control groups for reduction in the severity of cold symptoms (SMD −0.39; 95% CI −0.77 to −0.02) (P = 0.04). In all but two studies, the intervention started within 24 hours of onset of symptoms. In the studies by Douglas 1987 and Kurugol 2007 the intervention started within 24 to 48 hours after the onset of symptoms. In the study by Godfrey 1992 the authors found a significant decrease in the severity of symptoms when treatment was administered within 24 hours, compared to treatment administration within 48 hours. In the trial by Al-Nakib 1987, the zinc group had a significantly lower mean daily clinical score than the placebo group; the difference in scores attaining statistical significance by day four and day five of treatment. However, in the study conducted by Douglas 1987, there were no significant differences between the two groups. Two studies (Smith 1989; Weismann 1990) reported summed severity scoreswhich could not be pooled. One study (Smith 1989) found a reduction in summed severity score in the zinc group, whereas another (Weismann 1990) did not. Again the dosages, formulations and time of administration of zinc differed among the studies, and the studies also included both children and adults.

Figure 4.

Forest plot of comparison: 1 Primary outcomes, outcome: 1.2 Severity of symptoms (score).

Incidence of common cold

This was reported in two studies (Kurugol 2006b; Vakili 2009). The two studies used variable dose, formulation and duration of zinc use. The follow-up periods of the two studies were different, thereforewe based the calculation of the incidence rates on personyears. The person-time incidence rate is an appropriate measure of incidence when follow-up times are unequal (Rothman 1988). Incidence density is defined as the number of incident cases occurring in a susceptible population followed over a given time period; its units are therefore expressed as the number of cases per unit of person-time. The incidence density ratio is defined as the ratio of incidence density of an exposed group to that of an unexposed group. For each study, we calculated the incident rate ratio (IRR) of catching a cold in treatment participants compared to the risk in control participants (Analysis 1.3; Figure 5). The IRR of developing a cold in subjects who received the intervention was 0.64 (95% CI 0.47 to 0.88), compared to participants in the control group (P = 0.006).

Figure 5.

Forest plot of comparison: 1 Primary outcomes, outcome: 1.3 Incidence of common cold (IRR).

2. Secondary outcomes

Proportion of participants symptomatic after three, five or seven days of treatment
Proportion of participants symptomatic after three days of treatment

Three studies (Mossad 1996; Smith 1989; Weismann 1990) included a total of 340 participants. There was no significant difference between the intervention and control group for the proportion of participants symptomatic after day three of treatment (OR 0.81; 95% CI 0.27 to 2.42) (P = 0.7) (Analysis 2.1).

Proportion of participants symptomatic after five days of treatment

Three studies (Mossad 1996; Smith 1989; Weismann 1990) included a total of 340 participants. There was no significant difference between the intervention and control group for proportion of participants symptomatic after day five of treatment (OR 0.78; 95% CI 0.32 to 1.95) (P = 0.6) (Analysis 2.2).

Proportion of participants symptomatic after seven days of treatment

Five studies (Douglas 1987; Godfrey 1992; Mossad 1996; Smith 1989; Weismann 1990) included a total of 476 participants. There was a significant difference between the intervention and control group for proportion of participants symptomatic after day seven of treatment (OR 0.45; 95% CI 0.20 to 1.00) (P = 0.05) (Analysis 2.3).

Time to resolution of individual cold symptoms

This was reported in five studies.

Time to resolution of cough

Four studies (Kurugol 2006a; Macknin 1998; Prasad 2000; Prasad 2008) included a total of 453 participants (intervention = 219, control = 234). The time taken for resolution of cough was significantly shorter in the intervention group (SMD -0.55; 95% CI -1.04 to -0.05) (P = 0.03) (Analysis 2.4).

Time to resolution of nasal congestion

Five studies (Kurugol 2006a; Macknin 1998; Petrus 1998; Prasad 2000; Prasad 2008) included a total of 605 participants (intervention = 302, control = 303). The time taken for resolution of nasal congestion was significantly shorter in the intervention group (SMD -0.25; 95% CI -0.41 to -0.09) (P = 0.002) (Analysis 2.5).

Time to resolution of nasal drainage

Five studies (Kurugol 2006a; Macknin 1998; Petrus 1998; Prasad 2000; Prasad 2008) included a total of 599 participants (intervention = 298, control = 301). The time taken for resolution of nasal drainage was significantly shorter in the intervention group (SMD -0.32; 95% CI -0.62 to -0.01) (P = 0.04) (Analysis 2.6).

Time to resolution of sore throat

Four studies (Kurugol 2006a; Macknin 1998; Prasad 2000; Prasad 2008) included a total of 430 participants (intervention = 211, control = 219). The time taken for resolution of sore throat was significantly shorter in the intervention group (SMD -0.24; 95% CI -0.44 to -0.03) (P = 0.02) (Analysis 2.7).

Change in individual severity symptom scores
Change in cough symptom score

This was reported in two studies (Douglas 1987; Petrus 1998). In the study by Douglas 1987, a total of 63 treatment courses were evaluated (intervention = 33, control = 30) and the mean cough score (standard error of mean (SEM) not provided) was lower in the control group (6.3) than in the intervention group (10.6), which was statistically insignificant (P = 0.2). In the study by Petrus 1998, a total of 101 participants were included and there was a significant decrease in the mean cough score in the intervention group (SMD -2.84; 95% CI -3.4 to -2.28) (P < 0.00001) (Analysis 2.8).

Change in nasal symptom score

This was reported in four studies (Douglas 1987; Kurugol 2006a; Kurugol 2007; Petrus 1998). In the study by Douglas 1987, a total of 63 treatment courses were evaluated and the mean nasal score (SEM not provided) was lower in the control group (9.8) than in the intervention group (11.7), which was statistically insignificant (P = 0.5). In the study by Petrus 1998, a total of 101 participants were included and there was a decrease in the mean nasal score (not significant) in the intervention group (nasal congestion: placebo 1.43 ± 0.05, zinc 1.54 ± 0.08; nasal drainage: placebo 1.61 ± 0.07, zinc 1.45 ± 0.07). In the Kurugol 2006a and Kurugol 2007 studies a total of 314 participants were included and there was no difference between the two groups for the change in nasal symptom score (SMD -0.06; 95% CI -0.42 to 0.30) (P = 0.73) (Analysis 2.9).

Change in throat symptom score

This was reported in two studies (Douglas 1987; Petrus 1998). In one study (Douglas 1987), a total of 63 treatment courses were evaluated and the mean throat score (SEM not provided) was lower in the intervention group (6.1) than in the control group (6.2), which was statistically insignificant (P = 0.96). In another study (Petrus 1998), a total of 101 participants were included and there was a decrease in the mean throat score (not significant) in the intervention group (sore throat: placebo 1.34 ± 0.11, zinc 1.26 ± 0.06; scratchy throat: placebo 1.53 ± 0.08, zinc 1.38 ± 0.1).

School absenteeism

Three trials reported this outcome. The pooled result from the two preventive trials (Kurugol 2006a; Vakili 2009) showed that zinc supplemented children were absent for fewer days from school (SMD -0.37; 95% CI -0.7 to -0.04) (P = 0.03) (Analysis 2.10). In one of the therapeutic trials (Macknin 1998), children taking zinc were less likely to be absent than children taking placebo (OR 0.60; 95% CI 0.32 to 1.13) (P = 0.12).

Antibiotics use

Two trials reported this outcome (Kurugol 2006b; Vakili 2009). The antibiotic prescription was more likely in placebo than in zinc supplemented children (OR 0.27; 95% CI 0.16 to 0.46) (P < 0.00001) (Analysis 2.11).

Adverse events

Ten trials (Douglas 1987; Kurugol 2006a; Kurugol 2006b; Kurugol 2007; Macknin 1998; Mossad 1996; Prasad 2000; Prasad 2008; Smith 1989; Weismann 1990) were included for reporting of any or individual adverse events. The incidence of any adverse event was higher in the zinc group (OR 1.59; 95% CI 0.97 to 2.58) (P = 0.06) than in the control group (Analysis 2.12; Figure 6). Among individual events, bad taste (OR 2.64; 95% CI 1.91 to 3.64) (P < 0.00001) (Analysis 2.13) and nausea (OR2.15; 95%CI 1.44 to 3.23) (P = 0.002) (Analysis 2.14) had a higher incidence in the zinc group. There was no significant difference between the two groups in the incidence of constipation (P = 0.17) (Analysis 2.15), diarrhea (P = 0.08) (Analysis 2.16), abdominal pain (P = 0.25) (Analysis 2.17), dry mouth (P = 0.09) (Analysis 2.18) and oral irritation (P = 0.50) (Analysis 2.19).

Figure 6.

Forest plot of comparison: 2 Secondary outcomes, outcome: 2.12 Any adverse event.

Discussion

The discussion is divided into two parts: the first will discuss important methodological issues that have emerged from research in this area, and the second part will discuss the results obtained and their clinical significance.

Part 1: methodology

Since Eby's trial in 1984 (Eby 1984), 18 studies have investigated whether zinc is efficacious in the treatment or prevention of the common cold. Among these 15 studies were included in this review. The methodological quality of the included trials was rated as good, with two trials excluded because of poor quality. Eby's trial realised a number of limitations which raised concerns regarding the validity of the results. Treatment blinding in the trial has been questioned as zinc lozenges were found to be unpalatable, distorted the taste of participants and caused a higher incidence of side effects. In addition, investigators relied solely on the subjective assessment of cold symptoms; laboratory confirmation of viral infection was not conducted and analyses were only conducted on a subgroup of those originally enrolled in the trial. Eby's trial was nevertheless instructive and highlighted a number of methodological issues.

Like Eby's trial, most trials have relied on community-acquired infections. However, two trials recruited participants from volunteers experimentally inoculated with human rhinovirus (Al-Nakib 1987; Farr 1987a). While high rates of infection with human rhinovirus were attained in the later trials and most participants experienced cold symptoms, in trials relying on community-acquired infection, the infecting agent and the infection rates were generally not determined.

In trials relying on community-acquired infection, investigators relied on trial participants or family members to assess the incidence and severity of cold symptoms. Though in most of the trials information was generally provided on how compliance with the recording of symptoms was assessed, objective periodic assessments of the clinical severity of respiratory symptoms were not conducted. In the trials conducted by Al-Nakib (Al-Nakib 1987), Farr (Farr 1987a), Macknin (Macknin 1998) and Kurugol (Kurugol 2006a; Kurugol 2006b; Kurugol 2007) symptoms were assessed by trial personnel thus providing some assurance as to the validity of clinical severity scores and estimates based on such scores. Assessment of response to treatment also depended on objective measurements such as nasal mucus weight or tissue counts, which was measured in one study (Al-Nakib 1987) and the authors found that zinc gluconate reduced both of these parameters. However, as in most studies children were involved, this was not practical.

Research by Farr (Farr 1987b) suggested that in most trials the size of the placebo-blinding study used to determine whether zinc and placebo lozenges were indistinguishable was not sufficiently large to detect a significant difference. In their efforts to find a suitable matching placebo lozenge Farr showed that a false negative result may result if a small subject population (i.e. fewer than 20) is used. Given that placebo-blinding studies were only conducted in six of the 15 trials, and with the exception of three trials (Farr 1987a; Prasad 2000; Prasad 2008) the size of the placebo-matching studies in two of the remaining three trials (no information was provided on the size of placebo study conducted by Weismann (Weismann 1990)) ranged from eight to 20, the adequacy of blinding in most trials is questioned. Zinc-treated participants also experienced higher incidences of side effects, complaints or both, and in four trials, zinc-treated participants complained of altered, bad or unpalatable taste which suggests that zinc lozenges were distinct from placebo lozenges and, in this respect, blinding may have been compromised. However, the increased incidence of bad taste and nausea found by Mossad (Mossad 1996); constipation and mouth dryness found by Prasad (Prasad 2000) and bad taste, nausea, mouth, tongue or throat discomfort and diarrhea found by Macknin (Macknin 1998), may have been related to the use of different ligands (gluconate, acetate) rather than to zinc itself.

Much of the controversy surrounding the use of zinc lozenges in the treatment of the common cold has concerned whether formulations used in trials showing no benefit failed to release sufficient zinc ions to be effective. It has been hypothesised that there is a direct correlation between reductions in the duration of common cold symptoms and the daily dosage of all positively charged zinc species released from lozenges at physiologic pH (Eby 1995). The reanalysis of 10 double-blind, placebo-controlled zinc trials by solution chemistry methods showed a significant correlation between total daily dosages of positively-charged zinc species and a reduction in the mean duration of common colds (Eby 2004). Zinc gluconate and zinc acetate have very low chemical stability and mainly release positively charged zinc ions in aqueous solutions at physiologic pH, but stronger complexes do not (Eby 2004). Adding a strong zinc-binding ligand, such as glycine, citric acid, tartaric acid, mannitol and sorbitol, to a solution containing a zinc complex that is weakly bonded results in the sequestration of zinc to the stronger ligand, reducing or eliminating the benefits of zinc lozenges (Eby 2004). The extent to which the zinc ion was released from formulations reporting no benefit is not known. However, experimental evidence suggests that in saliva the ionisation of zinc to free zinc for some formulations may have been completely (Zarembo 1992) or partially (Farr 1988) suppressed. A formulation developed by Godfrey (Godfrey 1992) that incorporates glycine has been shown to release more than 50% of the zinc from zinc gluconate as the zinc ion. Results from trials conducted by Godfrey (Godfrey 1992) and Mossad (Mossad 1996) suggest this formulation reduced the duration and severity of respiratory symptoms; whereas the trial conducted by Macknin (Macknin 1998) and Turner (Turner 2000) suggest no effect of this formulation. The placebo-matching was inadequate; consequently the adequacy of blinding in all these four trials is questioned. Hatch et al (Hatch 1987), reported that zinc acetate releases essentially 100% of its zinc as Zn2+ ions at a physiological pH. Thus, use of zinc lozenges may be advantageous. Results from trials conducted by Petrus (Petrus 1998) and Prasad (Prasad 2000; Prasad 2008) suggest this formulation reduced the duration and severity of respiratory symptoms. These studies used compressed lozenges designed by George Eby that were identical in composition. In addition to zinc acetate, they contained directly compressible (agglomerated) dextrose as the tablet base, glycerol monostearate (2.5% of tablet weight) as the tablet lubricant, stevia for added sweetness, and peppermint oil for flavour, with the composition compressed to near maximal hardness for slowest dissolution. These ingredients were specifically chosen because they do not react with ionic zinc. The trials conducted by Douglas (Douglas 1987) using zinc acetate suggest no effect of this formulation. The placebo-matching and blinding were stated to be adequate in all the four trials. Three trials (Kurugol 2006a; Kurugol 2006b; Kurugol 2007) used syrup preparation of zinc (zinc sulphate) and found reduced duration and severity of respiratory symptoms without any increase in adverse effects in zinc group. Placebo-matching and adequacy of blinding was not stated in these two trials. Another trial (Vakili 2009) used tablet preparation (zinc sulphate) and found decreased incidence, fewer school absences, less antibiotic administration and no adverse effects in zinc-supplemented children. Again placebo-matching and adequacy of blinding was not stated in this trial.

The toxicology of zinc has been well characterised. The potential for elevated blood levels of zinc to disrupt copper metabolism and other nutrients preclude its long-term use in the treatment of the common cold (Pfeiffer 1980). Doses higher than 150 mg/day have also been associated with adverse effects (Chandra 1984). In addition, the higher incidence of side effects in zinc-treated participants will most likely limit the usefulness of zinc in the treatment of cold symptoms. In 11 trials (Douglas 1987; Kurugol 2006a; Kurugol 2006b; Kurugol 2007; Macknin 1998; Mossad 1996; Prasad 2000; Prasad 2008; Smith 1989; Vakili 2009; Weismann 1990) included for reporting of any or individual adverse events, the overall adverse events (OR 1.59; 95% CI 0.97 to 2.58) (P = 0.06) were higher in the intervention than in the control group, except in one trial (Vakili 2009). Among individual events, bad taste (OR 2.64; 95% CI 1.91 to 3.64) (P < 0.00001) and nausea (OR 2.15; 95% CI 1.44 to 3.23) (P = 0.002) had a significantly higher incidence in the zinc group.

Viral studies were only performed in six trials (Al-Nakib 1987; Douglas 1987; Farr 1987a; Kurugol 2006a; Kurugol 2006b; Kurugol 2007). While in-vitro studies suggest zinc inhibits viral replication and the concentration of zinc in saliva should be sufficient to induce such an effect, three trials (Al-Nakib 1987; Douglas 1987; Farr 1987a) found no effect of zinc on incidence or shedding of rhinovirus by study participants. In relation to this, trials by Farr and Douglas, found no effect of zinc in treatment of cold, while Al-Nakib found reduction in the clinical symptom score. From trial by Al-Nakib, it might be suggested that medication may have had an effect on signs and symptoms of the colds rather than on virus replication. If this is the case, it would be interesting to know whether zinc would also have the same effect on corona virus colds or, indeed, on colds caused by other respiratory viruses. This may be the future area of research in zinc and common cold trials. Trials by Kurugol (Kurugol 2006a; Kurugol 2006b; Kurugol 2007) did not study the effect of zinc on rhinovirus cold; rather they excluded colds due to influenza viruses from analysis and found that zinc is effective in the treatment of the common cold.

Part 2: results

Although most investigators required participants to record the clinical severity of symptoms each day and used similar scales against which to rate symptom severity (symptoms were rated as none, mild, moderate or severe), there was little commonality in summary estimates used by investigators to describe the duration, incidence and severity of respiratory symptoms. Consequently for some outcomes it was not possible to pool results. In addition, there was insufficient detail provided in most published papers to determine whether trials used similar criteria for rating the severity of each symptom and therefore it was not possible to standardise clinical severity scores across all trials.

Among 10 trials reporting the duration of cold symptoms, results could be pooled from six trials, which suggest that zinc significantly reduced the duration of cold in treated participants. Among six of these trials, two trials (Kurugol 2006a; Kurugol 2007) used syrup preparation at a daily dose of 30 mg, whereas four trials (Macknin 1998; Petrus 1998; Prasad 2000; Prasad 2008) used lozenge preparation at a daily doses varying from 90 mg to 160 mg. In the other three trials (Douglas 1987; Godfrey 1992; Mossad 1996), estimates of average cold duration were available. These three trials used lozenge preparation at a daily dose varying from 80 mg to 190 mg. The average duration of cold for zinc-treated participants was reduced by approximately 42% and 20% of that estimated for placebo-treated participants in trials conducted by Mossad and Godfrey, respectively. However, in the trial conducted by Douglas, the average duration for zinc-treated participants was found to be increased by approximately 57% of that estimated for placebo-treated participants. Results from five trials (Kurugol 2006a; Macknin 1998; Petrus 1998; Prasad 2000; Prasad 2008) could be pooled to find the time taken for resolution of individual symptoms, and the result suggests that zinc significantly shortens the duration of individual symptoms (cough, nasal drainage, nasal congestion and sore throat). In one trial (Kurugol 2007), the authors found no significant decrease in the individual symptoms in the zinc group; while in another trial (Godfrey 1992), incidence of cough and nasal symptoms (congestion, drainage) were significantly decreased in the zinc group.

Among 10 trials measuring the severity score of cold symptoms, results from five trials (Kurugol 2006a; Kurugol 2007; Petrus 1998; Prasad 2000; Prasad 2008) could be pooled. There was significant difference between the intervention and control group for reduction in the severity of cold symptoms. Al-Nakib (Al-Nakib 1987) and Douglas (Douglas 1987) provided estimates of mean clinical scores. However, estimates were not directly comparable. In the trial by Al-Nakib, the zinc group had a significantly lower mean daily clinical score than the placebo group; the difference in scores attaining statistical significance on days four and five. However, in the trial conducted by Douglas, there were no statistically significant differences between zinc and placebo groups with respect to mean nasal, throat and cough scores. Results of the trial conducted by Godfrey (Godfrey 1992) suggested treatment with zinc reduced the frequency and severity of cold symptoms, which was noticeable by day five and significant by day seven. Among four trials (Douglas 1987; Kurugol 2006a; Kurugol 2007; Petrus 1998) measuring individual symptom scores there was a significant reduction in the cough score, with nasal and throat score being variably affected. In the trial conducted by Smith 1989, the zinc group had lower symptom severity scores on days four to seven of treatment which was statistically significant (P = 0.02); but in the trial conducted by Weismann 1990, no statistically significant differences between the two groups were found by day six of treatment (P = 0.14). Among these 10 trials, trials using syrup preparation used a daily dose of 30 mg, whereas the trials using lozenge preparation used daily doses varying from 80 mg to 276 mg.

Among the two preventive trials measuring the incidence of the common cold (Kurugol 2006b; Vakili 2009), the incidence rate ratio (IRR) of developing a cold in participants who received the intervention was lower than in the placebo group. There was marked heterogeneity, therefore we used a random-effects model for analysing this outcome. The second trial, though a randomized controlled trial (RCT), was not of good methodological quality, but this was included in the analysis as it included a large number of participants. Even after excluding this trial from analysis, the result still favoured zinc supplementation. The first trial used zinc sulfate syrup at a daily dose of 15 mg for seven months, whereas the second trial used zinc sulfate tablet at a daily dose of 10 mg for five months.

The proportion of participants that were asymptomatic after three, five and seven days of treatment was reported in the trials conducted by Mossad (Mossad 1996), Weismann (Weismann 1990) and Smith (Smith 1989), and the proportion asymptomatic after seven days of treatment was reported in all but the trials conducted by Farr (Farr 1987a) and Al-Nakib (Al-Nakib 1987). Analyses were conducted on an intention-to-treat (ITT) basis. In the trial conducted by Mossad (Mossad 1996) participants were less likely to have cold symptoms after three and five days of treatment in the zinc-treated group. The Peto ORs for days three and five were 0.37 (95% CI 0.14 to 0.92) and 0.35 (95% CI 0.16 to 0.76), respectively. In the trials conducted by Weismann (Weismann 1990) and Smith (Smith 1989), the proportion of participants asymptomatic after three and five days in the zinc and placebo groups was similar. The test for heterogeneity attained statistical significance for day five, but not day three and consequently a combined OR for day five is not appropriate. The combined Peto OR for day three was not significant 0.97 (95% CI 0.62 to 1.5). In trials conducted by Mossad (Mossad 1996), Godfrey (Godfrey 1992) and Weismann (Weismann 1990), there were fewer participants in the zinc group who had cold symptoms after seven days. Although the Peto OR 0.53 (95% CI 0.38 to 0.75) obtained by pooling results from the trials conducted by Mossad (Mossad 1996), Weismann (Weismann 1990), Godfrey (Godfrey 1992), Smith (Smith 1989) and Douglas (Douglas 1987) indicated fewer participants in the zinc group had cold symptoms after seven days of treatment, the test for heterogeneity was statistically significant and therefore we did not pool the results.

In six trials (Godfrey 1992; Kurugol 2006a; Mossad 1996; Petrus 1998; Prasad 2000; Prasad 2008) with similar study designs, methodologies and efficacy assessments, zinc was found to be effective in reducing the duration and severity of common cold symptoms in healthy children and adults, when it was administered within 24 hours of the onset of symptoms. In another trial (Kurugol 2007) with similar study design, methodology and efficacy assessments, zinc was found to be effective in reducing the severity of common cold symptoms in healthy children (without any change in duration), when it was administered within 24 to 48 hours of the onset of symptoms. In the trial by Godfrey et al (Godfrey 1992), the authors found a significant decrease in the duration and severity of symptoms when treatment was administered within 24 hours, compared to treatment administration within 48 hours.

There are a number of potential sources of heterogeneity in results obtained from trials included in this review. Most trials relied on community-acquired infections in which the infecting agent was not identified and as such different agents may have been involved which may have differed in their sensitivity to zinc. The amount of zinc taken each day by participants varied across trials, and given that some formulations released less zinc ion than others the effective dose of zinc across trials was variable. Blinding of treatment may not have been adequately controlled in some trials, thereby increasing the potential for performance and detection bias to occur. The time from onset of cold symptoms to commencement of treatment ranged from one to three days. Given the beneficial effects noted in trials commencing treatment with zinc within 24 hours, the results from all the trials may not be comparable. Last but not the least is the fact that the lifestyle of the study population in all the trials was different and the results might have been affected to some degree by this factor.

Summary of main results

Studies reporting duration and severity of cold symptoms suggest that the intake of zinc is associated with a significant reduction in the overall duration and severity of common cold symptoms. A higher proportion of participants became asymptomatic by day seven of treatment with zinc. Duration of individual cold symptoms was also significantly reduced in the zinc group, though the individual symptom severity scores were not significantly affected by the intake of zinc. Zinc supplementation led to reduction in the incidence of common cold, decreased school absence and decreased the risk of antibiotic use when used for at least for five months. The incidence of adverse events was significantly higher in the zinc group with the syrup preparation being better tolerated than lozenges.

Overall completeness and applicability of evidence

The trials included in the analysis involved healthy children and adults of all ages (except infants) and both sexes. All 15 trials were conducted in upper-middle and high-income countries, where zinc deficiency is uncommon (including in young children). Therefore, the results of these trials may not be applicable to children and adults in low-income countries. In all the included trials, the main weakness of the data is that most trials, when presenting data, did not differentiate between cold due to rhinovirus and other viruses (as viral studies were not conducted in most of these trials). So it is unclear whether zinc helps those with rhinoviral cold or even cold due to other viruses. However, as rhinovirus is the most common aetiological agent of the common cold all over the world (in both low-income and high-income countries), it may be predicted that zinc might also help people living in low-income countries.

Quality of the evidence

The trial evidence included is generally of good quality, with a low risk of bias. All 15 studies were blinded, but placebo-blinding was adequately described in only six trials. In nine trials, zinc-treated participants complained of altered, bad or unpalatable taste which suggests that zinc lozenges were distinct from placebo lozenges and, in this respect, blinding may have been compromised. Allocation concealment was adequate in nine studies and unclear in five studies. Thirteen trials reported a low rate of loss to follow up. This suggests that the studies were of good quality. For all the outcomes, there was more than one study reporting the individual outcome. The majority were carefully conducted community trials, with active mechanisms to promote adherence to the intervention and both active and passive case finding.

Potential biases in the review process

All the included trials, as expected, measured the effect of zinc on the common cold. There was therefore the potential to miss trials which may have measured common cold as upper respiratory tract infection in secondary outcomes which were less publicised or less well-indexed within the electronic databases. We tried to avoid this by conducting a wide search and assessing the relevance of each paper identified in that search carefully. There are no other obvious sources of potential bias.

Agreements and disagreements with other studies or reviews

The important changes in this updated review in comparison to the previous version (Marshall 1999) include the following.

  • 1.Intake of zinc is associated with a significant reduction in the duration and severity of common cold symptoms.
  • 2.Duration of individual cold symptoms was also significantly reduced in the zinc group.
  • 3.The syrup and tablet preparation of zinc is better tolerated than lozenges.
  • 4.Zinc supplementation reduces incidence, school absenteeism and prescription of antibiotics in children with the common cold.

In the review conducted by Marshall (Marshall 1999), the included studies had following missing information, for which it was not possible to pool the results across the studies, and these included: although most investigators required participants to record the clinical severity of symptoms each day and used similar scales against which to rate symptom severity (symptoms were rated as none, mild, moderate or severe), there was little commonality in the summary estimates used by investigators to describe the duration, incidence and severity of respiratory symptoms. It was therefore only possible to determine the proportion of participants who were asymptomatic after three and five days of treatment for three trials and after seven days of treatment for five trials. Except one study (Godfrey 1992), duration of symptoms was not reported in the rest of the studies. Therefore, again it was not possible to pool the results for this outcome.

A review published in 2004 by Hulisz (Hulisz 2004), which was an overview of published articles through MEDLINE (1980 to 2003), concluded that zinc effectively reduces the duration and severity of common cold symptoms when administered within 24 hours of the onset of symptoms. The author also had some concerns regarding the clinical tests of zinc for the treatment of common colds being inconsistent, primarily because of study design, blinding and lozenge contents; early formulations of lozenges being unpalatable with a higher incidence of side effects.

Authors' conclusions

Implications for practice

Evidence shows that zinc is beneficial for the common cold in healthy children and adults living in high-income countries. Pooled results from the trials showed that zinc reduced the duration and severity of common cold symptoms when used therapeutically. Zinc also reduced the incidence of the common cold, school absence and antibiotic use in healthy children when used prophylactically. We could not find any trials conducted in low-income countries, so our results cannot be applied to people living in low-income countries. Also, all the studies included healthy participants; we could not find any evidence regarding use of zinc in participants at risk of developing the common cold. Given that some formulations (especially lozenges) produced side effects and not all formulations may be effective, the use of zinc to treat common cold symptoms is presently advised with caution.

Implications for research

Morbidity associated with the common cold is not trivial. The median duration of a cold episode is 7.4 days, with 25% of cases continuing for two weeks. The burden of the common cold is even more pronounced in individuals with chronic co-morbidities or clinical risk factors, including those with asthma and chronic obstructive pulmonary disease, the elderly, those with a history of otitis media or sinusitis, and those who are immunocompromised. Asthmatic children experience more cold episodes than non-asthmatic children, which is a common risk factor for acute asthma exacerbations. Future studies should therefore focus on the role of zinc in these populations rather than healthy people, as the results would be more meaningful for them.

To date no clinical trials of zinc for the common cold have been conducted in low-income countries. The assumption is that in these countries zinc deficiency may be prevalent and the results may be far more impressive. It is therefore important that before any firm conclusion is made, trials should be conducted in these countries. Furthermore, although the economic burden of the common cold in these populations may be less the vast majority of people live in such countries, potentially making the results more meaningful.

More clinical trials reporting clinically relevant outcomes in a standard format are also needed, analysing and presenting data in a manner that is appropriate and suitable for combining with other trial data in meta-analyses. Investigators also need to recognise the difficulties that have been encountered, particularly with respect to blinding and bioavailability (with various formulations).

Although laboratory confirmation of infection is desirable, in large community-based trials the costs associated with such investigations limit the extent to which serology can be undertaken. However, unlike trials relying on experimentally-induced rhinoviral colds, findings from large community-based trials will address issues relating to the diversity of and generalisability to the common cold.

In addition, given its toxicological profile, the potential for zinc to induce adverse effects at the doses participants are required to take also needs to be determined.

Acknowledgements

We wish to thank Ian IR Marshall, the previous author of this review. We acknowledge all the help and infrastructure provided by the Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh. We acknowledge the help provided by Elizabeth Dooley, Managing Editor and Sarah Thorning, Trials Search Co-ordinator of the Cochrane Acute Respiratory Infections Group, for the EMBASE search and getting full text articles of studies. We are very grateful to the referees Durhane Wong-Rieger, Craig Mellis, Mark Jones and Paul Little for their input in improving the quality of this updated review.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Al-Nakib 1987
Methods Double-blind, placebo-controlled randomized trial
Participants Healthy adults 18 to 50 years
Interventions Therapeutic trial: participants took 1 lozenge 2-hourly for 6 days Intervention group: zinc gluconate lozenges containing 23 mg zinc Placebo group: not stated Prophylactic trial : participants took 1 lozenge/2 waking hours for a total of 12 lozenges/day for 4.5 days. On the second day they were challenged with HRV-2 Intervention group: zinc gluconate lozenges containing 23 mg zinc Placebo group: not stated
Outcomes Severity of symptoms Mean daily nasal secretions Total tissue counts Viral shedding Biochemical and haematological parameters Trial 1: urinary zinc levels
Notes Although participants were stated to be healthy, no other exclusion criteria were stated
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias) High risk  
Allocation concealment (selection bias) Unclear risk B - Unclear
Blinding (performance bias and detection bias) All outcomes Low risk  
Incomplete outcome data (attrition bias) All outcomes Unclear risk There were no drop-outs or withdrawals
Selective reporting (reporting bias) High risk  
Other bias Unclear risk The zinc and placebo lozenges were gifted by RBS Pharma, Milan
Douglas 1987
Methods Double-blind, placebo-controlled randomized trial
Participants Healthy adults
Interventions Participants took 6 to 8 lozenges/day at 2nd-hourly intervals for a minimum of 3 days and maximum of 6 days if symptoms persisted. New course commenced after 2 weeks if symptoms persisted but type of treatment may differ. Consequently 33 zinc courses and 30 placebo courses Treatment group: zinc acetate lozenges containing 10 mg zinc Placebo group: lozenges contained sodium acetate
Outcomes Duration and severity of symptoms (nasal, throat or cough) Viral cultures
Notes Although adults were stated to be healthy, no exclusion criteria were stated
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias) Low risk  
Allocation concealment (selection bias) Low risk Used blocked randomisation of 4 blocks each. The code was broken twice (once in middle of study and then at the end of study)
Blinding (performance bias and detection bias) All outcomes Low risk  
Incomplete outcome data (attrition bias) All outcomes Low risk  
Selective reporting (reporting bias) Low risk  
Other bias Unclear risk The zinc and placebo lozenges were provided by Fauldings Ltd
Farr 1987a
Methods Double-blind, placebo-controlled trial
Participants Healthy adults
Interventions Trial 1: treatment consisted of initial loading dose of 2 lozenges 36 hours following inoculation with HRV-39, and thereafter 1 lozenge every 2 hrs for a total of 8 lozenges/day for 5 days Intervention group: zinc gluconate lozenges containing 23 mg zinc Placebo group: lozenges contained 0.00125 mg denatonium benzoate Trial 2: treatment consisted of initial loading dose of 2 lozenges 2 hours following inoculation with HRV-13, and thereafter 1 lozenge every 2 hrs for a total of 8 lozenges/day for 7 days Intervention group: zinc gluconate lozenges containing 23 mg zinc Placebo group: 0.0025 mg denatonium benzoate
Outcomes Severity and duration of symptoms Tissue counts Laboratory tests Infection rates
Notes Exclusion criteria were symptoms of any respiratory illness in the week before the study, a history of hay fever, any familiarity with the taste of either denatonium benzoate or zinc, a history of any chronic disease, pregnancy, lactation or an unacceptable contraceptive method in women of child-bearing potential, and known abuse of habit-forming drugs
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias) Low risk Each lozenge was wrapped in cellophane and packaged in an opaque polyethylene bottle bearing the study number, the number of subjects, the treatment day and dosing instructions
Blinding (performance bias and detection bias) All outcomes Low risk  
Incomplete outcome data (attrition bias) All outcomes Low risk  
Selective reporting (reporting bias) Low risk  
Other bias Unclear risk Partly funded by Bristol Myers Products, Hillside, NJ
Godfrey 1992
Methods Double-blind, placebo-controlled randomized trial
Participants Participants ranged in age from 18 to 40 years
Interventions Participants took 1 lozenge every 2 hours for up to 8 hours a day Treatment group: zinc gluconate lozenges containing 23.7 mg zinc. Placebo group: lozenges contained tannic acid, glycine and calcium saccharinate in an orange-flavoured, boiled candy base
Outcomes Frequency and severity of symptoms over 7 days
Notes Exclusion criteria were positive bacteriological throat culture, pregnancy, lactation, and diabetes mellitus
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias) Low risk  
Allocation concealment (selection bias) Low risk A pharmacist, using a randomisation table provided by the study statistician, packaged containers for individual participants with lozenges according to the production run number and subject identification number
Blinding (performance bias and detection bias) All outcomes Low risk  
Incomplete outcome data (attrition bias) All outcomes Low risk  
Selective reporting (reporting bias) Low risk  
Other bias Unclear risk The study was sponsored by Godfrey Science and Design, PA and by a grant from the Rorer Pharmaceutical corporation, PA, USA
Kurugol 2006a
Methods Double-blind, placebo-controlled trial
Participants Children aged 2 to 10 years
Interventions Therapeutic trial: children received syrup preparation of zinc twice daily for 10 days Intervention group: zinc syrup consisted of 1.32 gm zinc sulphate in 100 cm3 (15 mg of zinc in a 5 cm3 spoonful) and glycerin, glucose, sunset yellow, orange essence, nipajin Placebo group: similar to above, but lacking the zinc component
Outcomes Duration and severity of cold symptoms
Notes Children with chronic disease, immunodeficiency disorder, asthma and history of hypersensitivity were excluded
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias) Low risk  
Allocation concealment (selection bias) Low risk A statistical consultant programmed a computer-generated randomisation code and prepared the packages of medication
Blinding (performance bias and detection bias) All outcomes Low risk  
Incomplete outcome data (attrition bias) All outcomes Low risk  
Selective reporting (reporting bias) Low risk  
Other bias Low risk Berko Ilac Company, Turkey, supplied the active and placebo medications and digital thermometers. The company did not participate in designing the study, collecting and analysing the data, or in writing the report
Kurugol 2006b
Methods Double-blind, placebo-controlled trial
Participants Children aged 2 to 10 years
Interventions Prophylactic trial: children received syrup preparation of zinc once daily for 7 months. Intervention group: zinc syrup consisted of 1.32 gm zinc sulphate in 100 cm3 (15 mg of zinc in a 5 cm3 spoonful) and glycerin, glucose, sunset yellow, orange essence, nipajin Placebo group: similar to above, but lacking the zinc component
Outcomes Number of colds per study child Cold-related school absence Concomitant antibiotic use
Notes Children with chronic disease, immunodeficiency disorder, asthma and history of hypersensitivity were excluded
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias) Low risk  
Allocation concealment (selection bias) Low risk A statistical consultant programmed a computer-generated randomisation code and prepared the packages of medication
Blinding (performance bias and detection bias) All outcomes Low risk  
Incomplete outcome data (attrition bias) All outcomes Low risk  
Selective reporting (reporting bias) Low risk  
Other bias Low risk Berko Ilac Company, Turkey, supplied the active and placebo medications, and digital thermometers. The company did not participate in designing the study, collecting and analysing the data, or in writing the report
Kurugol 2007
Methods Double-blind, placebo-controlled trial
Participants Children aged 1 to 10 years
Interventions Participants were asked to take 1 spoonful syrup twice a day for 10 days Treatment group: zinc syrup consisted of 1.32 g of zinc sulfate in 100 ml (15 mg of zinc in 5 mL spoonful) and glycerin, glucose, sunset yellow, orange essence and nipajin as preservative Placebo group: identical to above, but lacking the zinc component
Outcomes Duration and severity of cold symptoms
Notes Exclusion criteria were: common cold symptoms for > 48 hours, immunodeficiency disorder, chronic disease, recent acute respiratory disease (diagnosed by a physician in the previous 2 weeks), zinc allergy, allergic disease or non-allergic rhinitis, positive culture for group A Streptococcus and a positive cell culture for influenza A or B viruses
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias) Low risk  
Allocation concealment (selection bias) Low risk A statistical consultant programmed a computer-generated randomisation code and prepared the packages of medication. The packages were identical in appearance except for the randomisation numbers. The packages were randomly distributed by the study nurse
Blinding (performance bias and detection bias) All outcomes Low risk  
Incomplete outcome data (attrition bias) All outcomes Low risk  
Selective reporting (reporting bias) Low risk  
Other bias Low risk Medications (active and placebo) and digital thermometers were supplied by Berko Ilaç, Turkey. The company did not participate in designing the study, collecting and analysing the data, or in writing the report
Macknin 1998
Methods Double-masked, placebo-controlled trial
Participants Students aged 6 to 16 years in grades 1 through to 12
Interventions Students asked to take zinc lozenges, 10 mg, orally dissolved, 5 times a day (in grades 1 to 6) or 6 times a day (in grades 7 to 12) until their cold symptoms had been completely resolved for 6 hours Treatment group: zinc gluconate lozenges containing 10 mg zinc in a 3.75 gm hard candy that also contained sucrose, corn syrup, glycine Placebo group: lozenges contained calcium lactate pentahydrate instead of zinc and had similar composition as above
Outcomes Duration of resolution and severity of symptoms
Notes Subjects were excluded if they had an oral temperature greater than 37.7 ºC, had previously taken the zinc preparation, were pregnant, had a known immune deficiency, any acute illness other than common cold (e.g. pneumonia, gastroenteritis) or cold symptoms lasting more than 24 hours
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias) Low risk  
Allocation concealment (selection bias) Low risk A computer-generated randomisation code was provided to the pharmacist, who held the code and prepared the packages of medication
Blinding (performance bias and detection bias) All outcomes Low risk  
Incomplete outcome data (attrition bias) All outcomes Low risk  
Selective reporting (reporting bias) Low risk  
Other bias Unclear risk The study was supported by a grant from the Quigley Corporation, Doylestown, Pa
Mossad 1996
Methods Double-blind, placebo-controlled trial
Participants Participants were older than 18 years of age
Interventions Subjects took 1 lozenge 2-hourly for every waking hour Treatment group: zinc gluconate lozenges containing 13.3 mg zinc Placebo group: lozenges contained 5% calcium lactate
Outcomes Duration and severity of cold symptoms
Notes Exclusion criteria were pregnancy, immune deficiency or symptoms of the common cold for more than 24 hours prior to interview. Subjects were assessed for non-adherence to treatment; reasons for non-adherence were: participants had taken antibiotics, condition diagnosed by physician to be other than the common cold, participants filled in diaries from memory, or insufficient lozenges were taken (i.e. fewer than 4 per day for the first 4 days)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias) Low risk  
Allocation concealment (selection bias) Low risk A statistical consultant prepared a computer-generated randomisation code and the packages of medication
Blinding (performance bias and detection bias) All outcomes Low risk  
Incomplete outcome data (attrition bias) All outcomes Low risk  
Selective reporting (reporting bias) Low risk  
Other bias Low risk The study was supported by grants from the General Pediatrics Research Fund and the Departments of Infectious Diseases and General Pediatrics of the Cleveland Clinic Foundation
Petrus 1998
Methods Double-blind, placebo-controlled trial
Participants Participants were 18 to 54 years of age
Interventions Participants were instructed to use a lozenge every 1.5 hours while awake during day 0, then 1 lozenge every 2 hours while awake on following days while symptoms were present for 14 days or 6 hours after disappearance of last symptoms Treatment group: zinc acetate lozenges containing 9 mg zinc in a 2.7 g dextrose base Placebo group: lozenges contained sucrose octaacetate (0.169 mg)
Outcomes Duration and severity of symptoms
Notes Participants were excluded if they had a serious illnesses, organ transplants or disability (including HIV infection)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias) High risk  
Blinding (performance bias and detection bias) All outcomes Low risk  
Incomplete outcome data (attrition bias) All outcomes Low risk  
Selective reporting (reporting bias) Low risk  
Other bias Unclear risk Funded by Weider Nutrition International, Salt Lake City, Utah
Prasad 2000
Methods Double-blind, placebo-controlled trial
Participants Participants were older than 18 years of age
Interventions Participants were asked to use 1 lozenge every 2 to 3 hours while awake for as long as they had symptoms Treatment group: zinc acetate lozenges containing 12.8 mg zinc Placebo group: lozenges contained 0.25 mg of sucrose octaacetate, 6 mg of peppermint oil, 16 mg silica gel, 3877.75 mg dextrose DC and 100 mg glycerol monostearate
Outcomes Duration of symptoms Plasma levels of zinc and pro inflammatory cytokines
Notes Exclusion criteria were pregnancy, underlying immunodeficiency, chronic illness, symptoms of common cold for more than 24 hours, or had previously used zinc lozenges to treat common cold
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias) Low risk A research consultant prepared the randomisation code and the packages of medication
Blinding (performance bias and detection bias) All outcomes Low risk  
Incomplete outcome data (attrition bias) All outcomes Low risk  
Selective reporting (reporting bias) Low risk  
Other bias Low risk Funded partly by George and Patsy Eby Research Foundation. The research foundation had no role in the collection, analysis, or interpretation of the data or in the decision to publish the study
Prasad 2008
Methods Double-blind, placebo-controlled trial
Participants Participants were older than 18 years of age
Interventions Participants were asked to use one lozenge every 2 to 3 hours while awake for as long as they had symptoms Treatment group: zinc acetate lozenges containing 13.3 mg zinc in a hard candy that contained 3.8 g of sucrose and corn syrup Placebo group: lozenges contained 0.25 mg of sucrose octaacetate
Outcomes Duration of symptoms Plasma levels of zinc and pro inflammatory cytokines
Notes Exclusion criteria were pregnancy, underlying immunodeficiency, chronic illness, symptoms of common cold for more than 24 hours, or had previously used zinc lozenges to treat common cold
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias) Low risk A research consultant prepared the randomisation code and the packages of medication
Blinding (performance bias and detection bias) All outcomes Low risk  
Incomplete outcome data (attrition bias) All outcomes Low risk  
Selective reporting (reporting bias) Low risk  
Other bias Low risk Funded by National Institutes of Health; George and Patsy Eby Foundation, Austin, Texas (unrestricted research funds to Wayne State University for partial support)
Smith 1989
Methods Double-blind, placebo-controlled trial
Participants Participants were older than 18 years
Interventions Participants took a loading dose of 4 lozenges then took 2 every 2 hours for 7 days or 24 hours after disappearance of last symptoms Treatment group: zinc gluconate lozenges containing 11.5 mg zinc Placebo group: lozenges contained sucrose octaacetate
Outcomes Duration and severity of symptoms
Notes Participants were excluded if they had a serious acute or chronic medical condition, seasonal allergies, productive cough, required antibiotic therapy or had taken any treatment for symptoms within 8 hours of baseline assessment
Risk of bias
BiasAuthors' judgementSupport for judgement
Blinding (performance bias and detection bias) All outcomes Low risk  
Incomplete outcome data (attrition bias) All outcomes Low risk  
Selective reporting (reporting bias) Low risk  
Other bias Unclear risk The study was supported by a grant from McNeil Consumer Products Company
Vakili 2009
Methods Double-blind, placebo-controlled trial
Participants School children aged 6.5 to 10 years
Interventions Participants took tablet daily for 6 days a week for 5 months Treatment group: zinc sulfate tablets containing 10 mg zinc Placebo group: not defined
Outcomes Occurrence and duration of common cold
Notes The subjects were free of chronic diseases, such as sickle cell disease or protein-energy malnutrition
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias) High risk  
Incomplete outcome data (attrition bias) All outcomes Low risk  
Selective reporting (reporting bias) Low risk  
Other bias Low risk This study was supported by grant of vice president for research, Mashhad University of Medical Sciences
Weismann 1990
Methods Double-blind, placebo-controlled randomized trial
Participants Participants were aged 18 to 65 years
Interventions Participants took 1 lozenge at 1 to 1.5-hourly intervals Treatment group: zinc gluconate lozenges (in maltitol syrup) containing 4.5 mg zinc Placebo group: lozenges contained maltitol syrup with natural flavour
Outcomes Overall assessment of clinical condition assessed by participants using a visual analogue scale
Notes No exclusion criteria stated
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias) High risk  
Allocation concealment (selection bias) Unclear risk B - Unclear
Blinding (performance bias and detection bias) All outcomes Low risk  
Incomplete outcome data (attrition bias) All outcomes Low risk  
Selective reporting (reporting bias) Low risk  
Other bias Unclear risk The lozenges were manufactured and supplied by a firm

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion
Eby 1984 The trial was rated of poor methodological quality. A higher incidence of side effects and complaints in the zinc group may have reduced compliance with treatment (no information was provided on whether compliance with treatment was assessed). Intention-to-treat analyses were not conducted; analyses were only conducted on a subset of those originally enrolled in the trial. The trial relied on subjective assessment of symptoms by subjects. Inclusion criteria were not adequately addressed and therefore there may have been potential for selection bias to occur. In addition, no information was provided on how allocation to treatment groups was concealed, the power of the study was not stated and viral studies were not conducted
McElroy 2003 Poor methodological quality. Not a randomized trial
Potter 1993 Poor methodological quality. Not a randomized trial
Turner 2000 Poor methodological quality. Not a randomized trial
Veverka 2009 Poor methodological quality. Measured upper respiratory tract infection as a whole (common cold and seasonal flu)

Data and analyses

Download statistical data

Table Comparison 1. Primary outcomes
Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Duration of cold symptoms 6 762 Std. Mean Difference (IV, Random, 95% CI) -0.97 [-1.56, -0.38]
2 Severity of cold symptoms 5 513 Std. Mean Difference (IV, Random, 95% CI) -0.39 [-0.77, -0.02]
3 Incidence of common cold 2 1522 Risk Ratio (M-H, Random, 95% CI) 0.64 [0.47, 0.88]
Figure Analysis 1.1.

Comparison 1 Primary outcomes, Outcome 1 Duration of cold symptoms.

Figure Analysis 1.2.

Comparison 1 Primary outcomes, Outcome 2 Severity of cold symptoms.

Figure Analysis 1.3.

Comparison 1 Primary outcomes, Outcome 3 Incidence of common cold.

Table Comparison 2. Secondary outcomes
Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Number of participants symptomatic after 3 days of treatment 3 340 Odds Ratio (M-H, Random, 95% CI) 0.81 [0.27, 2.42]
2 Number of participants symptomatic after 5 days of treatment 3 340 Odds Ratio (M-H, Random, 95% CI) 0.78 [0.32, 1.95]
3 Number of participants symptomatic after 7 days of treatment 5 476 Odds Ratio (M-H, Random, 95% CI) 0.45 [0.20, 1.00]
4 Time to resolution of cough 4 453 Std. Mean Difference (IV, Random, 95% CI) -0.55 [-1.04, -0.05]
5 Time to resolution of nasal congestion 5 605 Std. Mean Difference (IV, Fixed, 95% CI) -0.25 [-0.41, -0.09]
6 Time to resolution of nasal drainage 5 599 Std. Mean Difference (IV, Random, 95% CI) -0.32 [-0.62, -0.01]
7 Time to resolution of sore throat 4 430 Std. Mean Difference (IV, Fixed, 95% CI) -0.24 [-0.44, -0.03]
8 Change in cough symptom score 1 101 Std. Mean Difference (IV, Fixed, 95% CI) -2.84 [-3.40, -2.28]
9 Change in nasal symptom score 2 314 Std. Mean Difference (IV, Fixed, 95% CI) -0.06 [-0.42, 0.30]
10 School absenteeism (days) 2 394 Std. Mean Difference (IV, Random, 95% CI) -0.37 [-0.70, -0.04]
11 Antibiotic use 2 394 Odds Ratio (M-H, Fixed, 95% CI) 0.27 [0.16, 0.46]
12 Any adverse event 5 796 Odds Ratio (M-H, Random, 95% CI) 1.59 [0.97, 2.58]
13 Bad taste 9 1062 Odds Ratio (M-H, Fixed, 95% CI) 2.64 [1.91, 3.64]
14 Nausea 8 932 Odds Ratio (M-H, Fixed, 95% CI) 2.15 [1.44, 3.23]
15 Constipation 7 874 Odds Ratio (M-H, Fixed, 95% CI) 1.60 [0.82, 3.10]
16 Diarrhoea 6 764 Odds Ratio (M-H, Fixed, 95% CI) 1.89 [0.92, 3.89]
17 Abdominal pain 6 824 Odds Ratio (M-H, Fixed, 95% CI) 1.31 [0.83, 2.07]
18 Dry mouth 7 874 Odds Ratio (M-H, Fixed, 95% CI) 1.37 [0.95, 1.99]
19 Mouth irritation 7 822 Odds Ratio (M-H, Fixed, 95% CI) 1.15 [0.77, 1.73]
Figure Analysis 2.1.

Comparison 2 Secondary outcomes, Outcome 1 Number of participants symptomatic after 3 days of treatment.

Figure Analysis 2.2.

Comparison 2 Secondary outcomes, Outcome 2 Number of participants symptomatic after 5 days of treatment.

Figure Analysis 2.3.

Comparison 2 Secondary outcomes, Outcome 3 Number of participants symptomatic after 7 days of treatment.

Figure Analysis 2.4.

Comparison 2 Secondary outcomes, Outcome 4 Time to resolution of cough.

Figure Analysis 2.5.

Comparison 2 Secondary outcomes, Outcome 5 Time to resolution of nasal congestion.

Figure Analysis 2.6.

Comparison 2 Secondary outcomes, Outcome 6 Time to resolution of nasal drainage.

Figure Analysis 2.7.

Comparison 2 Secondary outcomes, Outcome 7 Time to resolution of sore throat.

Figure Analysis 2.8.

Comparison 2 Secondary outcomes, Outcome 8 Change in cough symptom score.

Figure Analysis 2.9.

Comparison 2 Secondary outcomes, Outcome 9 Change in nasal symptom score.

Figure Analysis 2.10.

Comparison 2 Secondary outcomes, Outcome 10 School absenteeism (days).

Figure Analysis 2.11.

Comparison 2 Secondary outcomes, Outcome 11 Antibiotic use.

Figure Analysis 2.12.

Comparison 2 Secondary outcomes, Outcome 12 Any adverse event.

Figure Analysis 2.13.

Comparison 2 Secondary outcomes, Outcome 13 Bad taste.

Figure Analysis 2.14.

Comparison 2 Secondary outcomes, Outcome 14 Nausea.

Figure Analysis 2.15.

Comparison 2 Secondary outcomes, Outcome 15 Constipation.

Figure Analysis 2.16.

Comparison 2 Secondary outcomes, Outcome 16 Diarrhoea.

Figure Analysis 2.17.

Comparison 2 Secondary outcomes, Outcome 17 Abdominal pain.

Figure Analysis 2.18.

Comparison 2 Secondary outcomes, Outcome 18 Dry mouth.

Figure Analysis 2.19.

Comparison 2 Secondary outcomes, Outcome 19 Mouth irritation.

Appendices

Appendix 1. EMBASE.com search strategy

24. #20 AND #23

23. #21 OR #22

22. random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR 'cross-over':ab,ti OR volunteer*:ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR ((doubl* OR singl*) NEAR/2 (blind* OR mask)):ab,ti

21. 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'crossover procedure'/exp

20. #13 AND #19

19. #14 OR #15 OR #16 OR #17

18. 'trace element':ab,ti OR 'trace elements':ab,ti OR 'trace mineral':ab,ti OR 'trace minerals':ab,ti

17. micronutrient*:ab,ti

16. 'trace element'/de

15. zinc:ab,ti OR zn:ab,ti

14. 'zinc'/exp

13. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12

12. urti:ab,ti OR uri:ab,ti

11. 'upper respiratory tract infection':ab,ti OR 'upper respiratory tract infections':ab,ti OR 'upper respiratory infection':ab,ti OR 'upper respiratory infections':ab,ti

10. 'upper respiratory tract infection'/de

9. rhinit*:ab,ti

8. 'rhinitis'/de

7. coryza:ab,ti

6. rhinovir*:ab,ti

5. 'rhinovirus infection'/de

4. 'rhinovirus'/exp

3. 'common cold symptom'/exp

2. 'common cold':ab,ti OR 'common colds':ab,ti

1. 'common cold'/exp

Feedback

Zinc for the common cold feedback: the Eby 1984 report, flavor and flavor masking issues, and what is next, 23 February 2011

Summary

My congratulations are extended to Meenu Singh and Rashmi R Das for a very comprehensive review of the zinc for common cold literature.  However, some comments are needed concerning the Eby et al. 1984 report, flavor issues and where we need to go next.

Concerning the original 1984 Eby, Davis and Halcomb article

Our original 1984 article[1] started this line of inquiry by showing that it was possible to shorten common colds by 7 days (P = 0.0005) with 23 mg zinc (zinc gluconate) lozenges when taken each two wakeful hours.  These lozenges (unflavored and unsweetened dietary supplement tablets) lasted about 30 minutes in the mouth which provided sufficient time for local absorption into oral tissues. This protocol was developed after observing that 50 mg zinc (zinc gluconate) tablets slowly dissolved in the mouth of a 3-year old child with acute lymphocytic leukemia (T-cell) resulted in her severe common colds disappearing within 2 hours without further treatment and many similar informal observations in the general community.

Our report has drawn some criticism, mainly since the taste of the zinc gluconate lozenges was modestly objectionable resulting in more dropouts in the zinc-treated group than in the placebo-treated group.  Bias would occur if zinc-treated subjects who received little or no benefit selectively dropped out or failed to return reports. We were concerned about this potential for bias, and to protect our results we estimated the maximum effect of such bias by assuming that all dropouts and all non-reporters in both zinc and placebo treatment groups received no benefit and responded as if they were on placebo.  The effect of zinc in that analysis remained substantial and statistically strong (P = 0.007), and this potential bias was shown to be irrelevant.  These modifications to our main results were published in our Discussion section on page 23 right-hand column, but they have been ignored in reviews by others, thus adversely biasing results of several critical reviews.   Therefore, I am disappointed that this error was also committed by Singh and Das.

Flavor and flavor-masking issues

Concern about blinding evolved from concern over “bad taste” of zinc lozenges.  There is much difference in the taste of zinc lozenges, which should be considered in evaluating bias.  Zinc gluconate in tablets with no other soluble ingredients1 are moderately objectionable tasting, but tolerable, to most people.  Zinc gluconate releases 72% of its zinc as ionic zinc at physiologic pH 7.4.[2]  Zinc gluconate can be sweetened without bitterness using a fructose tablet base as was done in the Al-Nakib trial at the Great Britain Common Cold Unit.[3]  However, mixing zinc gluconate with any other sweetener, especially sucrose and/or dextrose, results in products that age within 30 days to be as bitter as the bitterest substance known, sucrose octaacetate.  This unexpected and adverse effect caused researchers to search for alternatives to zinc gluconate and for ways to flavor-mask zinc gluconate.  Extreme bitterness likely affected only the results of Weisman et al., although they compensated by using very small amounts of zinc.[4]

Although pure zinc acetate, which releases 100% ionic zinc at physiologic pH 7.4,2 tastes vastly more vile than pure zinc gluconate, it is easily flavor-masked by a variety of sweeteners in either hard-candy compositions such as the lozenges tested by Prasad et al.[5] or compressed tablets as tested by Prasad et al.[6] and Petrus et al.[7]  These zinc acetate lozenges did not contain flavor-masking additives.  Zinc acetate tastes and works best when present in a 1:100 ratio with dextrose in very highly compressed tablets which last about 30 minutes when being dissolved in the mouth.  One failure occurred in effervescent lozenges containing zinc acetate which were flavor-masked with tartaric acid and sodium bicarbonate, resulting in elimination of ionic zinc.[8],[9]

Citric acid was used to flavor-mask the objectionable taste of zinc gluconate in a corn syrup and sucrose hard candy lozenge.[10]  Citric acid has a high affinity for ionic zinc and no zinc ions were available for absorption into oral tissues, resulting in clinical failure.2 Due to its pleasant taste, this formula is commonly used in commercial zinc lozenges in the United States resulting in no effect against common colds other than nutritional support.

Glycine was used to flavor-mask zinc gluconate in several clinical trials, with two[11],[12] showing efficacy and one[13] showing lack of efficacy.  Variability in results may have been caused by glycine since it eliminates about one half (or more) of the ionic zinc from lozenges.2  NOTE:  This formula does not release “over 90% ionic zinc” at physiologic pH 7.4 as portrayed by Sing and Das, but it does release that amount at pH 5.0, a nonsense pH.

Availability of ionic zinc is dependent upon a number of variables including pH, concentration, temperature and compound being tested, and such is a subject of extensive research by solution equilibrium inorganic chemists .2

Consequently, to say that effective zinc lozenges have an objectionable taste that can bias clinical trials is not necessarily factual.  The worst possible taste and most bias in effective zinc lozenges results from zinc gluconate in a non-fructose carbohydrate hard candy or tablet base, which was found only in the Weisman trial.4  Zinc gluconate in a non-soluble tablet base is about 1/10th as objectionable,1 while zinc gluconate in a fructose tablet base,3 zinc gluconate-glycine11, 12, 13 and zinc acetate5,6,7 in a 1:100 dextrose tablet base are each commercially acceptable in taste.  However, zinc acetate lozenges are potentially the most effective, use the least zinc, and are the best tasting.   Zinc acetate lozenges also had the least potential for bias due to their pleasant taste, although they had an astringent mouth-feel demonstrating release of zinc ions.  A perfect placebo would have been astringent in mouth-feel, perhaps like tannin.  Pursuit of a pleasant tasting and effective zinc lozenge has led to both clinical successes and failures, and the large variety of formulations has greatly complicated the analytical picture.

What is next? 

As the researcher that originally discovered the effect of ionic zinc from throat lozenges on the duration of common colds, I am very concerned that the statement “zinc is good for colds” released on nearly every U.S. national TV news program, radio station and newspaper (and perhaps also in Europe, Australia and elsewhere) due to loose journalistic interpretation of the Singh and Das report.  It  is far too broad and too simplistic to be accurate, and it will likely lead to OTC products that will not have the features necessary to shorten colds more than a day, thus 26 years of zinc lozenge research could be lost and perhaps not regained for decades or a century.  These features were previously described in my 2009 review.2  That review showed dose-response linearity of lozenges by their ionic zinc content on the duration of colds.  It showed that reductions in the mean (P=0.001) and median (P=0.004) durations of common colds were statistically significant and meaningful.

It also showed that the effects of a compressed dextrose tablet containing 18 mg of zinc (zinc acetate dyhydrate - 60 mg), glycerol monostearate as a tablet lubricant and peppermint oil on silica gel, which happens to be a 2X homeopathic Zincum aceticum formula, is expected to shorten common colds by 7 days.   These lozenges released the same amount of ionic zinc as did our 23 mg zinc gluconate lozenges tested in 1984.1  They are 1.9 cm (¾ inch) diameter and 1.27 cm (1/2 inch) thick tablets which are best produced on heavy production machines like a Stokes 328-2 tablet press.  Magnesium stearate was not used as a lubricant due to concerns about concentrated magnesium greatly stimulating rhinovirus replication.[14]

These zinc acetate lozenges are pleasant tasting and taste like peppermint candy.  If these tablets are compressed to a sufficient hardness, they will dissolve in the mouth in about 30 minutes.  Fick's laws of membrane permeability show that the amount of a solute absorbed across a membrane is time and concentration dependent.   Thirty minutes is a reasonable time for oral dissolution.  Also, the dextrose-based formula does not excessively promote saliva production.  I suggest that it is now time to focus on this basic formulation and go forward with research on it.  I see no necessity to focus on zinc compounds that do not release 100% of their zinc as ionic zinc, or on products that dissolve too fast for significant oral absorption, or on products that contain too little ionic zinc to be effective.  From the time of contact with the oral mucosa aspects of Fick's laws, the use of syrups or orally ingested tablets to treat common colds are not advised if large reductions in their duration are desired.

Perhaps there is also a requirement to consider how ionic zinc works in shortening colds and the work of Merluzzi et al. in showing that ionic zinc, but not bound zinc, inhibits the replication of rhinoviruses should be considered vital,[15] along with the extensive pioneering work of Korant and Butterworth in showing the inhibitor effects of ionic zinc on rhinoviral replication.[16], [17],[18], [19], [20], [21], [22], [23]  These articles should give support to the notion that the main effect of ionic zinc in treating common colds is by rhinovirus replication inhibition.

Although I cannot see into the future, I have proposed here what I believe to be the most likely route to successful treatment of common colds, and I hope that new zinc lozenge researchers will follow my advice.  If they do follow my advice, they should be able to demonstrate in a coordinated manner the massive benefits of zinc in treating colds in just a few years, rather than in the decades or centuries that I expect from future distortions of the literature if researchers continue to test faulty products and publish those results.  Provided with good results, manufactures can follow through with products that will shorten colds by a week in the general public.  Then, and only then, can we say that there is a cure for the common cold!

[1] Eby GA, Davis DR, Halcomb WW.  Reduction in duration of common colds by zinc gluconate lozenges in a double-blind study. Antimicrob Agents Chemother. 1984;25:20-4.

[2] Eby GA.  Zinc lozenges as cure for the common cold--a review and hypothesis.  Med Hypotheses. 2010;74:482-92.

[3] Al-Nakib W, Higgins PG, Barrow I, Batstone G, Tyrrell DA. Prophylaxis and treatment of rhinovirus colds with zinc gluconate lozenges. J Antimicrob Chemother. 1987;20:893-901.

[4] Weismann K, Jakobsen JP, Weismann JE, Hammer UM, Nyholm SM, Hansen B, Lomholt KE, Schmidt K.  Zinc gluconate lozenges for common cold. A double-blind clinical trial.  Dan Med Bull. 1990;37:279-81.

[5] Prasad AS, Beck FW, Bao B, Snell D, Fitzgerald JT.  Duration and severity of symptoms and levels of plasma interleukin-1 receptor antagonist, soluble tumor necrosis factor receptor, and adhesion molecules in patients with common cold treated with zinc acetate.  J Infect Dis. 2008;197:795-802.

[6] Prasad AS, Fitzgerald JT, Bao B, Beck FW, Chandrasekar PH.  Duration of symptoms and plasma cytokine levels in patients with the common cold treated with zinc acetate. A randomized, double-blind, placebo-controlled trial.  Ann Intern Med. 2000;133:245-52.

[7] Petrus, EJ, Lawson KA, Bucci LR, Blum K.  Randomized, Double-Masked, Placebo-Controlled, Clinical Study of the Effectiveness of Zinc Acetate Lozenges on Common Cold Symptoms in Allergy-Tested Subjects. Current Therapeutic Research. 1998;59:595 – 607.

[8] Douglas RM, Miles HB, Moore BW. Failure of effervescent zinc acetate lozenges to alter the course of upper respiratory tract infections in Australian adults. Antimicrobial Agents and Chemotherapy. 1987;31:1263-1265.

[9] Eby GA.  Chapter 4.C.2.  Handbook for Curing the Common Cold: The Zinc Lozenge Story. George Eby Research. Austin. 1994.  Accessed February 22, 2011.  http://web.archive.org/web/20080622211606/http://george-eby-research.com/html/handbook-for-curing-the-common-cold.html

[10] Farr BM, Conner EM, Betts RF, Oleske J, Minnefor A, Gwaltney JM Jr.  Two randomized controlled trials of zinc gluconate lozenge therapy of experimentally induced rhinovirus colds.  Antimicrob Agents Chemother. 1987;31:1183-7.

[11] Godfrey JC, Conant Sloane B, Smith DS, Turco JH, Mercer N, Godfrey NJ.  Zinc gluconate and the common cold: a controlled clinical study.  J Int Med Res. 1992;20:234-46.

[12] Mossad SB, Macknin ML, Medendorp SV, Mason P.  Zinc gluconate lozenges for treating the common cold. A randomized, double-blind, placebo-controlled study.  Ann Intern Med. 1996;125:81-8.

[13] Macknin ML, Piedmonte M, Calendine C, Janosky J, Wald E.  Zinc gluconate lozenges for treating the common cold in children: a randomized controlled trial.  JAMA. 1998;279:1962-7.

[14]  Fiala M, Kenny GE. Effect of magnesium on replication of rhinovirus HGP.  J Virol 1967;1:489–93.

[15]  Merluzzi VJ, Cipriano D, McNeil D, Fuchs V, Supeau C, Rosenthal AS, Skiles JW.  Evaluation of zinc complexes on the replication of rhinovirus 2 in vitro.  Res Commun Chem Pathol Pharmacol. 1989;66:425-40.

[16] Korant BD, Butterworth BE. Inhibition by zinc of rhinovirus protein cleavage: interaction of zinc with capsid polypeptides. J Virol 1976;18:298–306.

[17] Korant BD, Kaurer JC, Butterworth BE. Zinc ions inhibit replication of rhinoviruses. Nature 1974;248:588–90.

[18] Butterworth BE, Grunert RR, Korant BD, et al. Replication of rhinoviruses. Arch Virol 1976;51:169–89.

[19] Korant BD, Butterworth BE. Inhibition by zinc of rhinovirus protein cleavage. Interaction of zinc with capsid polypeptides. Chem Abstr 1976;85:76. Abs. 85:814y.

[20] Korant BD. Role of cellular and viral proteases in the processing of picornavirus proteins. In: Perez-Bercoff R, editor. The molecular biology of picornaviruses. New York: Plenum Publishing; 1979.

[21] Korant BD. Inhibition of viral protein cleavage. In: Gauri KK, editor. Design of inhibitors of viral functions. New York: Academic Press; 1979.

[22] Butterworth BE, Korant BD. Characterization of the large picornaviral polypeptides produced in the presence of zinc ion. J Virol 1974;14:282–91.

[23] Korant BD, Kauer JC, Butterworth BE. Molecular basis of zinc as a viral inhibitor. In: Risby TH, editor. Ultratrace metal analysis in biological sciences and environment. Washington, DC: American Chemical Society; 1979.

Reply

We thank Dr Eby for his comment on the review as well as giving his expert opinion on the future direction of zinc cold research. Addressing the issue of bias that has occurred in their trial (which has also been highlighted in many other reviews), we want to point out that, though the author (Eby et al) have discussed about the bias resulting from increase drop out in their study in the designated paragraph described above, it should be noted that there are many drawbacks in their trial that make the quality score of a trial poor (please refer to the Cochrane handbook on bias before giving good score to a randomized clinical trial and thus qualifying them for inclusion in a review).

Regarding Dr Eby's description of how zinc acts in the treatment of common cold, it is very true that it is the ionic zinc that plays major role and we hope that authors of future trials will take these issues into account before any meaningful conclusion can be drawn from a particular trial (we have also highlighted these facts in the present review). However, this mechanism might not play important role in the preventive act of zinc for the common cold. But, as zinc has been found in clinical trials to have preventive role for the common cold (zinc also has role in prevention of lower respiratory tract infection/pneumonia, found in a recent Cochrane review), other mechanisms might play role, including enhancement of innate as well as acquired immunity and correction of underlying zinc deficiency. Only future research in this area can answer these questions.

Contributors

George Eby

Comment from Ronald Turner, 1 March 2011

Summary

The authors of this review state that our paper (Turner RB, Cetnarowski WE.  Effect of treatment with zinc gluconate or zinc acetate on experimental and natural colds. Clin Infect Dis 2000;31:1202-1208) was excluded for poor methodology as the study was not randomized.  The study was in fact randomized as stated in the methods section of the paper. If there was confusion on this issue, I would have gladly supplied the original study protocol to the authors of this review.

Submitter agrees with default conflict of interest statement:

I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.

Reply

This paper by Turner et al, though described as a randomized trial, was exclude because of the poor quality score (not because of randomization only, as commented by the author).

Contributors

Ronald Turner

Are we really sure zinc is an effective treatment for the common cold?, 3 March 2011

Summary

We are concerned regarding a number of aspects of this updated review on the use of Zinc for the treatment and prevention of the common cold[1]. The review concludes that “zinc is beneficial for the common cold in healthy children and adults living in high-income countries.” We are concerned that the threats of potential biases on the review have not been considered carefully enough.

Below we include contour enhanced funnel plots[2] of the two primary treatment outcomes of the review – duration of illness and severity of symptoms (see Figure).

Figure: Funnel plots for the two primary treatment outcomes in the review (http://dl.dropbox.com/u/21306757/funnel_plot_zinc.jpg)

Although these plots contain relatively small numbers of studies (6 and 5 respectively), there is a concerning trend in both graphs that the smaller the trials the increasingly larger the effect sizes observed. Additionally, the most precise studies (towards the top of the plots) have effect sizes which are either 0 or very close to it. One possible explanation, and we acknowledge this is not the only explanation, for such “small study effects” trends is publication bias, which would imply that outcomes from trials with less beneficial/harmful effects have been suppressed. This could be due to the suppression of whole trials which have never been published, or, it could be due to suppression of particular outcomes from certain trials (outcome reporting bias)[3] or a combination of the two. Outcome reporting bias is perhaps a particular concern because we infer from the review that 13 treatment trials (including 1 trial excluded from the statistical overview[4]) were identified but only 10 studies reported on each of the primary outcomes, with fewer trials still reporting both outcomes. From this initial position of potential outcome reporting bias, further selection occurred to include these trials into each meta-analysis (6 and 5 respectively), because the review authors believe the results were not reported in a compatible format, although we suggest that it may well be possible to include at least one further study [5] reporting a dichotomous version of the outcome using previously described methods[6, 7]. Some of these studies excluded from the meta-analysis are discussed in the results section, with at least one study having no effect (Douglas 1987[8] for severity of symptoms).  Unusually for a review with small study effects, the studies identified as being industry-sponsored are the largest, but are also those closer to the null effect suggesting much smaller effects. The smaller studies indicating greater effects are noted as medical research foundation sponsored, which may support an alternative explanation to the one we propose.

The authors identified heterogeneity between studies and thus used random effects models in the meta-analysis. As this model gives more weight to the smaller, imprecise, studies (than the fixed effect one), in the presence of funnel plot asymmetry, this has the effect of producing larger effect sizes than the fixed effect alternative; both estimates with their 95% confidence intervals are included on the figure (although both approaches will lead to statistically significant benefits of zinc)[9]. With so few studies, alternative formal approaches to unpicking the heterogeneity, such as meta-regression on dose or dose-duration values would be difficult to undertake.

In the methods section, the authors report making an assessment of publication bias “by examining the funnel plot for asymmetry” and reference a highly cited paper on testing for publication bias[10]. Curiously, there is no further mention or discussion of the results of any assessment for publication bias in the paper. While any formal test on the data is likely to have low power due to the relatively small numbers of studies[6], we believe scrutinising the above funnels is helpful, although the asymmetry is so extreme we initially identified the problem simply by looking at the presented forest plots.

Additionally, we do not understand the author's statement that “we assessed risk of bias due to selective reporting of outcomes for the study as a whole, rather than for each outcome” For the reasons outlined above, we think some outcome specific consideration would be helpful.

The authors conclude their assessment of “Potential biases in the review process”, that although there was the potential that they may have missed studies referring to the common cold as upper respiratory tract infection, “there are no other obvious sources of potential bias”, we urge the authors to reconsider this statement. In light of the above, and particularly considering the data presented on side effects, we would like to suggest that the conclusions of this review are toned down taking into account the threat of potential reporting biases.

A further issue to have come to light in examining this meta-analysis is that the primary outcome – duration of cold symptoms – is stated to be measured in days. However, the meta-analysis is conducted using the standardised mean difference. If all studies measure the outcome on the same scale (days) it is unclear why the outcome needed standardising and the results would be better presented on the (untransformed) mean difference scale where clinical interpretation is much easier and less strong statistical assumptions are required.

References

[1] Singh M, Das RR. Zinc for the common cold. Cochrane Database of Systematic Reviews 2011:Art. No.: CD001364. DOI: 10.1002/14651858.CD001364.pub3.

[2] Peters JL, Sutton AJ, Jones DR et al. Contour enhanced funnel plots help distinguish publication bias from other causes of asymmetry. Journal of Clinical Epidemiology 2008; 67:991-996.

[3] Chan A-W, Hróbjartsson A, Haahr MT et al. Empirical evidence for selective reporting of outcomes in randomized trials. Comparison of protocols to published articles. Journal of the American Medical Association 2004; 291:2457-2465.

[4] Farr B, Conner E, Betts R et al. Two randomized controlled trials of zinc gluconate lozenge therapy of experimentally induced rhinovirus colds. Antimicrobial Agents and Chemotherapy 1987; 31:1183-1187.

[5] Smith DS, Helner EC, Nutall CE et al. Failure of zinc gluconate in treatment of acute upper respiratory tract infections. Antimicrobial Agents and Chemotherapy 1989; 33:646-648.

[6] Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.0.2 [updated September 2009]. The Cochrane Collaboration; 2009.

[7] Chinn S. A simple method for converting an odds ratio to effect size for use in meta-analysis. Statistics in Medicine 2000; 19:3127-3131.

[8] Douglas R, Miles H, Moore B et al. Failure of effervescent zinc acetate lozenges to alter the course of upper respiratory tract infections in Australian adults. Antimicrobial Agents and Chemotherapy 1987; 31:1263-1265.

[9] Poole C, Greenland S. Random-effects meta-analysis are not always conservative. American Journal of Epidemiology 1999; 150:469-475.

[10] Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. British Journal of Medicine 1997; 315:629-634.

Submitter agrees with default conflict of interest statement:

I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.

Reply

Thanks for pointing out some important issues related to the review. We also have the same concern regarding the final conclusion (which we have discussed more or less in the review) and that's why no recommendation could presently be made on use of zinc for the common cold. Regarding the publication bias, we agree with the authors (Jaime L Peters, Santiago G Moreno, Bob Phillips, Alex J Sutton) that publication bias could not be ruled out which might also compromise the findings of the present review. But what's important is that, though publication bias alerts to the problem, they do not provide a solution to it. Moreover, funnel plots have their own limitations. So, what Eby et al described above regarding the future direction is more important, as they provide a solution to the problems in the zinc common cold research. But in the next updated version, we will add the funnel plot. Regarding the application of random and/or fixed model effect in the meta-analysis, they have their inherent problems. Last concern regarding inclusion of MD instead of SMD, we have replied it below [actually, the MD for the duration of cold is -1.48 (around 2 days)].

Contributors

Yours sincerely

Jaime L Peters, Santiago G Moreno, Bob Phillips, Alex J Sutton.

Comment from Christopher Cates, 7 March 2011

Summary

Dear Sir,

I have not personally started taking zinc tablets for the common cold, as I do not think the average answer tells me enough to justify a change in practice (too much heterogeneity and a very wide predictive interval [-4.2 to 1.2 days when analyzed as mean difference]. See method in: Riley RD, Higgins JPT, Deeks JJ. Interpretation of random effects meta-analyses. BMJ. 2011;342:d549). Prasad seems to me to be measuring something different to the other studies, as the mean difference of 3 days in these studies is incompatible with all the other study results?

It would be easier for readers to understand these results if they were presented as a mean difference in days (rather than SMD).

Surely the overall average result is of limited usefulness when there is such diversity between the study results?

Yours faithfully.

Submitter agrees with default conflict of interest statement:

I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.

Reply

The mean difference (in days) for the duration of cold is -1.48 (around 2 days). We agree with the authors regarding the heterogeneity of results, as a result of which no recommendation was possible about zinc for the common cold (already described in conclusion).

Contributors

Chris Cates

MA FRCGP

Comment from Catherine McIlwain, 14 March 2011

Summary

I'd like to request that one line of text (“Zinc inhibits rhinoviral replication”) in the plain language summary be restated in simpler terms.  That phrasing resulted in quite a few comments from consumers who don't understand virus replication.

If you are amenable to a change, I would recommend using the word ‘virus’ instead of ‘rhinoviral’ throughout the plain language summary.  In addition, would it be acceptable to change ‘rhinoviral replication’ to ‘the spread of the virus’ only in the plain language summary, of course.

Submitter agrees with default conflict of interest statement:

I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.

Reply

No. replication and spread of virus does not mean necessarily the same thing. But we can say it as follows: zinc inhibits replication of common cold virus.

Contributors

Catherine McIlwain

The zinc for the common cold review by Singh and Das has a number of problems which should be considered when the review is next time updated, 5 September 2011

Summary

1) Search of the studies:

Eby and Halcomb (2006) reported a randomized double-blind placebo-controlled trial on zinc for the common cold [1], which is missing from the review. The trial is included in MEDLINE (PMID: 16454145) and Singh and Das should have found it and listed among the trials requiring an assessment.

2) Extraction of data:

Singh and Das describe that “The lead review author (MS) entered data directly into Review Manager. An independent coder verified accuracy of data entry”. However, looking at their Analysis 1.1 led me to wonder how can they claim that the findings of the Petrus (1998) trial were non-significant (the 95% CI covering the “no effect”), given that Petrus (1998 p. 600) wrote that “t-test showed that the mean duration of all symptoms was significantly lower in the zinc group (3.8±0.2 days) than in the placebo group (5.1±0.4 days)(P+0.008)”. In their Analysis 1.1, Singh and Das give the mean duration of colds in the zinc group as 4.4 days, and not as the 3.8 days reported by Petrus (above). The value of 4.4 days is given in the Petrus (1998) Table II as the overall mean duration of colds, i.e. the mean for all zinc and placebo participants combined, but Table II also gives the 3.8 days for the duration of colds in the zinc group. In their paper, Petrus (1998) gives the accuracy of the mean as the SE (standard error), whereas the Review Manager needs the SD (standard deviation). The SE values reported by Petrus (1998) are highly inaccurate (above), yet Singh and Das calculated the corresponding SD estimates from them. To get the accurate Petrus (1998) trial results, I contacted the statistician of the group and got their  results: 3.797 (SD 1.630) days in the zinc group and 5.106 (SD 2.955) in the placebo group (Ken Lawson, email 4 Mar 2009). The Petrus (1998) values in Analysis 1.1 should be replaced with these correct and accurate values.

3) The characteristics of included studies table:

In the Characteristics of included studies table, Singh and Das write about the Al-Nakib (1987) trial that there was “unclear risk” for the item “incomplete outcome data addressed?”.  However, Singh and Das write that “there were no drop-outs or withdrawals”. Lack of drop-outs does not justify their judgment (“unclear risk”). Furthermore, Singh and Das state that in the Al-Nakib trial there is “high risk” for the item “free of selective reporting?”. The statement that there is “high risk” calls for justification, whereas none is given. Furthermore, Singh and Das list six outcomes for the Al-Nakib (1987) trial, yet only one of them is relevant to the review: “the severity of symptoms”. However, I cannot see this outcome in any of their Analysis tables. The outcome section of the included studies table should list only those outcomes that are used in the review. Furthermore, it would help the reader if the included studies table describes in which Analysis the values of the outcomes are presented. Singh and Das state that in the Smith (1987) trial there is “low risk” for the item “incomplete outcome data addressed?”. Smith started with 176 participants and reported the results for only 110 participants, which means that they reported data for only 62% of the initial participants. In their Methods section, Singh and Das write that “we considered that incomplete outcome data had been adequately addressed if 85% or more of the participants were included in the analysis, or if less than 85% were included but adequate steps were taken to ensure or demonstrate that this did not bias the results.” In their included studies table, Singh and Das do not describe why the analysis of 62% of initial participants is acceptable for the Smith (1987) trial although they give the limit of 85% in their Methods. Stating that the Smith (1987) trial has “low risk” with the 38% drop-out rate, and the  Al-Nakib (1987) trial has “unclear risk” with no drop-outs (above) is puzzling. Singh and Das use an inclusion criterion “randomized controlled trials”. Weismann (1990) did not report the method of allocation in their trial report. Nevertheless, Singh and Das describe in their  included studies table the Weismann (1990) trial: “Methods: randomized trial”. Since their report did not describe the method of allocation, I contacted Kaare Weismann, who wrote to me “It was a consequetive  allocated study with the same number of patient in the two groups” (email 2 Jul 2010). Thus, the Weismann (1990) trial was not randomized. Given their inclusion criteria, Singh and Das should exclude the Weismann trial or they should re-write the inclusion criteria so that they also include pseudo-randomized trials which have used, for example, alternative allocation. Furthermore, Singh and Das state that there is “unclear risk” for the item “allocation concealment?” in the Weismann (1990) trial, even though the trial was double blind. The term double-blind means that both the patients and researchers are unaware of the type of treatment until the trial is concluded. Consequently, neither of them can know to which group a patient had been allocated. Thus, double-blind means that there must have been allocation concealment. Otherwise the patients and researchers could not remain blind after randomization. This same error is seen in the description of the Al-Nakib (1987) and Petrus (1998) trials, which also were double-blind trials. As a consequence of this error, Figure 1 gives an impression that several studies were methodologically less satisfactory than they actually were. More details of the trials should be given in the included studies table. For example, in their “implications for practice”, Singh and Das state that “We could not find any trials conducted in low-income countries, so our results cannot be applied to people living in low-income countries.” However, three trials by Kurugol (2006a, 2006b, 2007) were carried out in Turkey, and one trial by Vakili (2009) was carried out in Iran. These are low-income countries. According to World Bank statistics, the GDP per capita in Turkey and Iran is 80% and 90% lower than in Germany, as an example. Thus, the above statement is false although there are countries which are much poorer than Turkey and Iran. To help the reader to understand the contexts of the trials, it would be useful to describe the country and the settings of the trials. Such information affects the generalization of the findings. Studies in Turkey and Iran cannot be directly extrapolated, for example, to the western countries.

4) The characteristics of excluded studies table:

In the Characteristics of excluded studies table, Singh and Das comment on the Eby (1984) trial: “Intention-to-treat analyses were not conducted; analyses were only conducted on a subset of those originally enrolled in the trial.” However, this is also true for the Smith (1987) trial, which included only 62% of the initial participants in the analysis (above). Eby (1984 p. 20-21) described: “Of 146 original volunteers, 120 subjects returned reports. Initially, to use as much of the data as possible, we analyzed the 80 complete reports from 108 subjects who had been ill for 10 days or less at the start of treatment. ...  this report is restricted to those 65 subjects who reported being ill for 3 days or less before starting the experiment.” Singh and Das use an inclusion criterion “interventions commenced within three days of participants developing common cold symptoms”. Given such a criterion, Eby's post-randomization restriction to 65 subjects who were ill for 3 days or less before the treatment started is relevant data. In any case, Singh and Das should treat Eby (1984) and Smith (1987) trials consistently, so that both are included or excluded on the basis of the high rate of participants not included in the analysis. Singh and Das further criticise the Eby (1984) trial: “The trial relied on subjective assessment of symptoms by subjects.” However, this applies to essentially all zinc and common cold studies. In evidence-based medicine, the subjective symptoms are most essential outcomes. Subjective symptoms determine whether a patient goes to work or school, stays at home, or visits a physician. Double-blinding prevents systematic bias in the subjective assessment of symptoms, and therefore “subjective” per se cannot cause bias in a double-blind trial. Furthermore, if Singh and Das consider that “subjective assessment” is a basis to exclude the Eby (1984) trial, they should apply the same criterion to the other trials. Singh and Das also comment on the Eby (1984) trial: “Inclusion criteria were not adequately addressed and therefore there may have been potential for selection bias to occur.” In randomized trials, the primary concern is the comparability of trial arms, so that there are no systematic differences that could lead to bias. All randomized trials use inclusion criteria of some kind, but that has nothing to do with the question whether the trial arms are comparable. Inclusion criteria are relevant when we consider the possibility to generalize the results, but not when considering the internal validity of a trial. Finally, Singh and Das conclude their criticism of the Eby (1984) trial: “In addition, no information was provided on how allocation to treatment groups was concealed, the power of the study was not stated and viral studies were not conducted”.  First, in most other zinc and common cold studies there is no information about how allocation was concealed (i.e. how blinding was maintained). Second, statistical power is relevant when planning a trial, but not after the trial is concluded, since the confidence interval gives the same information. Third, given that the primary goal in evidence-based medicine is to find out whether a treatment has clinically important effects, viral studies are not relevant. All these issues are missing in most of the zinc and common cold studies. Thus, if Singh and Das consider that these arguments give a sound basis to exclude the Eby trial, they should apply the same criteria also to the other trials. In the Characteristics of excluded studies table, Singh and Das comment on the Turner (2000) trial: “Poor methodological quality. Not a randomised trial”. However, Turner writes “Subjects who met the criteria for randomization to treatment were randomly assigned to 1 of the 4 treatments in accordance with the drug-randomization code” (p. 1202), [for induced colds:] “Subjects were randomized to receive study medication 24 h after challenge if they had a total daily symptom score ≥ 3” (p. 1203), [for natural colds:] “Subjects who presented to the study sites with a common-cold illness of ≤ 1 calendar day's duration (effectively 36 h), reported ≥ 2 different symptoms, and had a total symptom score of ≥ 2 were randomized to receive 1 of the 3 treatments” (p. 1203).Thus, the statement by Singh and Das is false, unless they have information that disproves the text of the Turner (2000) report. In such a case, they should present their evidence. The Turner (2000) trial was reported as a randomized placebo-controlled double-blind study, and there is no basis to claim that it was of “poor methodological quality”.

5) Different methods of administering zinc should be analyzed separately:

The majority of the zinc trials examined zinc lozenges in the western countries. Three trials by Kurugol (2006a, 2006b, 2007) and one trial by Vakili (2009) administered zinc as syrup or tablets; however, all these trials were carried out in low-income countries, Turkey and Iran. Thus, it is possible that the benefit of zinc supplementation in these trials is caused by biological mechanisms that are different from the mechanisms of the zinc lozenges, which are intended to be dissolved slowly in the mouth. The daily dose of zinc in the Kurugol and Vakili studies varied from 10 to 30 mg per day, whereas the total daily dose of zinc in the zinc lozenge studies varied from 30 to 207 mg per day [2]. Thus, it is possible, or probable, that the benefits of the low dose zinc supplementation found by Kurugol and Vakili are explained by a sub-optimal dietary intake of zinc by children in Turkey and Iran. In contrast, it is possible that high dose zinc is needed in the lozenges to get benefit from them. Although Singh and Das restrict their systematic review to tablets, syrup and lozenges, they should also take a look at the other zinc literature. A few studies have examined the use of nasal administration of zinc to treat colds and found significant benefit [3,4]. Still, patients should not be exposed to intranasal zinc, since there are cases of anosmia caused by such a therapy [5]. Nevertheless, the benefit of local application of zinc to the nose indicates that the effect of zinc lozenges may be caused by local effects in the mouth-throat region, instead of systemic effects such as those caused by the ingestion of tablets and syrup. Therefore it is inappropriate to pool the tablet and syrup trials with the lozenge trials. This is a good example of the apples and oranges problem.

6) The duration of the common cold should not be dichotomized:

Singh and Das present three tables which show “number of participants symptomatic after N days of treatment”, N being 3, 5 and 7. Dichotomization of continuous variables has been criticized [6]. Moreover, there is no need to dichotomize the duration of colds when analyzing the zinc lozenge trials. Although several trials did not report the mean and SD for the duration of colds in the trial arms, all of them reported data that makes it possible to calculate the mean and SD for cold duration [2].  The use of continuous outcome for common cold duration would also simplify the review as three redundant tables can be removed.

7) Duration of the common cold should be normalized so that placebo groups have length 100%:

There is substantial variation in the duration of colds in the placebo groups of the zinc lozenge trials, from 5.1 days to 9.0 days and 10.8 days [2]. Although part of this variation is evidently caused by random variation, it is also caused by actual variations in the severity of disease in different patient groups and in differences in outcome definitions. Therefore, the relative effect of zinc on the common cold duration should be calculated in percentages, because the relative effect partly adjusts for the variations between patient groups and outcome definitions.   For example, if a 6-day cold is shortened by 1 day, it is not equivalent to a 1-day cold being shortened by the same amount although both differences are equal in absolute units. Consequently, it is much more reasonable to calculate the relative effect of zinc, so that a 6-day cold shortened by 2 days and a 1-day cold shortened by 0.33 days both correspond to an equivalent 33% reduction. Calculating the relative effect corresponds to the normalization of all control groups to an episode duration of one unit or 100%.  Therefore, in our Cochrane review on vitamin C and the common cold we calculate the relative effect [7]. The use of relative effect in the analysis of common cold duration corresponds to using the risk ratio in the analysis of binary data. In their Analysis 1.1, Singh and Das pool the results by the SMD method, which means normalizing the duration by the SD (i.e. 1 unit in the scale corresponds to the SD of each study). However, using such a scale (SD units) is very difficult for an ordinary reader to understand. In their abstract, Singh and Das write: “Intake of zinc is associated with a significant reduction in the duration (standardised mean difference (SMD) -0.97)”. However, reporting should always give the unit of the measurement. In the SMD method, the unit is the SD unit. Thus, the above sentence should be re-written more accurately: “zinc shortened the duration of colds by 0.97 SD units”. Such accurate reporting would reveal the main problem of the SMD procedure: what does the SD-unit mean? I pooled the results of three large-dose zinc acetate lozenge trials and I found that “zinc shortened the duration of colds by 42%” [2], which is easy to understand. Most people can form an opinion whether 42% is small or large, but few people can form an opinion whether 0.97 SD units is small or large, or whether it is more or less than 42%. Thus, a relative scale would make the analysis of zinc trials easier to understand for the ordinary readers compared with the SD scale. The Cochrane Handbook comments (9.2.3.2): “The standardized mean difference [SMD] is used as a summary statistic in meta-analysis when the studies all assess the same outcome but measure it in a variety of ways (for example, all studies measure depression but they use different psychometric scales).” Thus, the SMD can be useful, for example, in psychiatry. In the case of common cold duration, the relative effect in percentages is much easier for readers.

8) Subgroup analysis should be carried out:

Singh and Das write in the Background section that a “significant correlation between total daily dosages of positively charged zinc species and a reduction in the mean duration of common colds” has been reported. Therefore, the daily dose of zinc should be considered in the statistical analysis. However, in their Result section Singh and Das claim that “subgroup analysis was not possible as there were not enough studies for each variable.” This is not correct.  As noted above, there is a 6-fold variation in the total zinc dose (30 to 207 mg per day [2]) in the zinc lozenge studies. Given that the results of the zinc lozenge trials diverge so that some found no effect whereas some others found highly significant benefit, the relation between the dose and effect should be analyzed. Dose-response relation is a basic concept in pharmacology. I analyzed 13 zinc lozenge trials and divided them into three subgroups on the basis of the total daily dose of zinc and the type of lozenge [2]. None of five trials with the lowest doses of zinc found benefit of the lozenge, suggesting that they may have been using too low a dose. In the high-dose trials, greater benefit was seen in three trials with zinc acetate, and smaller benefit in five non-acetate trials [2]. Further research should focus, in particular, on high doses of zinc acetate (providing 80-90 mg/day of zinc) [2]. Thus, subgroup analysis is possible and it indicates a path to research that is needed. The syrup and tablet studies with children in the low-income countries should be presented as a separate group, on a separate Analysis table.

9) Pooling the adverse effects of all zinc trials is unsound:

Eby has pointed out that the adverse effects of zinc lozenges, such as bad taste, can be explained largely by the differences in the composition of the lozenges [8-10]. In their Discussion, Singh and Das acknowledge this possibility: “the increased incidence of bad taste and nausea ...  may have been related to the use of different ligands (gluconate, acetate) rather than to zinc itself.” In addition, it is obvious that dissolving a high zinc dose lozenge slowly in the mouth causes different adverse effects compared with ingesting a low zinc dose tablet or syrup straight to the stomach. Nevertheless, Singh and Das combine the adverse effects of the tablet and the zinc lozenge trials together as if they could estimate a “universal adverse effect of zinc” in the dose range of 15 to 192 mg per day. Nevertheless, the lack of “mouth irritation” by zinc syrup in the Kurugol studies (Analysis 2.19) is fully uninformative for a reader who is interested in the possible adverse effects of zinc lozenges. Thus, it would be much more informative to summarize the adverse effects as text, instead of pooling the results of such different trials. In the most recent zinc acetate lozenge trial, there were no significant differences between the zinc and placebo groups in the occurrence of adverse effects although the daily dose was 92 mg (Prasad 2008). Thus, it seems possible to formulate zinc lozenges that have minimal adverse effects. Furthermore, a patient suffering from acute adverse effects such as bad taste can simply stop taking the lozenges, whereas those who don't suffer from such adverse effects could benefit from the lozenges. Although Singh and Das restrict their systematic review to treating the common cold, they should also take a look at other zinc literature for information about zinc safety. For certain patients, zinc has been administered at high doses, 150 mg/day, for therapeutic purposes for months [2,11-12].  On the basis of such long-term studies with high zinc doses, there does not seem to be any basis for assuming that treating the common cold for a week with high doses of zinc (80-90 mg/day) in the form of lozenges might cause unanticipated harm.

10) Credit should be given to earlier work on the same topic:

In their Introduction, Singh and Das write “The last review of all available RCTs of zinc for the common cold was published in 1999”, which is erroneous. Although it is not reasonable to discuss in detail all the earlier literature on the topic, the main reviews should be cited and briefly commented. Jackson's [13] and Caruso's [14] systematic reviews on zinc and the common cold were published after 1999. In the Discussion section, RevMan proposes a subtitle “Agreements and disagreements with other studies or reviews”. Evidently, the same issue can be discussed under some other title. In any case, it would be important for Singh and Das to describe to what extent their review agrees and disagrees with the earlier reviews, such as [13,14]. If the conclusions do not differ from earlier reviews, then a new review does not increase our understanding about the topic. If the conclusions are different, then the reasons for the differences should be briefly discussed.

References

[1] Eby GA et al. Ineffectiveness of zinc gluconate nasal spray and zinc orotate lozenges in common-cold treatment: a double-blind, placebo-controlled clinical trial. Altern Ther Health Med 2006;12:34-8.http://www.ncbi.nlm.nih.gov/pubmed/16454145

[2] Hemilä H. Zinc lozenges may shorten the duration of colds: a systematic review. Open Respir Med J 2011;5:51-8.http://dx.doi.org/10.2174/1874306401105010051

[3] Hirt M et al. Zinc nasal gel for the treatment of common cold symptoms: a double-blind, placebo-controlled trial. Ear Nose Throat J 2000;79:778-82.http://www.ncbi.nlm.nih.gov/pubmed/11055098

[4] Mossad SB. Effect of zincum gluconicum nasal gel on the duration and symptom severity of the common cold in otherwise healthy adults. QJM 2003;96:35-43.http://dx.doi.org/10.1093/qjmed/96.1.35

[5] Alexander TH et al. Intranasal zinc and anosmia: the zinc-induced anosmia syndrome. Laryngoscope 2006;116:217-20 and 1721-3.http://dx.doi.org/10.1097/01.mlg.0000191549.17796.13

[6] Royston P et al. Dichotomizing continuous predictors in multiple regression: a bad idea. Stat Med 2006;25:127-41.http://dx.doi.org/10.1002/sim.2331

[7] Hemilä H et al. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev 2010:CD000980.http://dx.doi.org/10.1002/14651858.CD000980.pub3

[8] Eby GA. Zinc ion availability - the determinant of efficacy in zinc lozenge treatment of common colds. J Antimicrob Chemother 1997;40:483-93.http://www.ncbi.nlm.nih.gov/pubmed/9372416

[9] Eby GA. Zinc lozenges: cold cure or candy? Solution chemistry determinations. Biosci Rep 2004;24:23-39. http://dx.doi.org/10.1023/B:BIRE.0000037754.71063.41

[10] Eby GA. Zinc lozenges as cure for the common cold – a review and hypothesis. Med Hypotheses 2010;74:482-92. http://dx.doi.org/10.1016/j.mehy.2009.10.017

[11] Hallböök T et al. Serum-zinc and healing of venous leg ulcers. Lancet 1972;2:780-2. http://dx.doi.org/10.1016/S0140-6736(72)92143-5

[12] Simkin PA. Oral zinc sulphate in rheumatoid arthritis. Lancet 1976;2:539-42. http://dx.doi.org/10.1016/S0140-6736(76)91793-1

[13] Jackson JL et al. Zinc and the common cold: a meta-analysis revisited. J Nutr 2000;130(5S Suppl):1512S-5S. http://jn.nutrition.org/cgi/reprint/130/5/1512S 

[14] Caruso TJ et al. Treatment of naturally acquired common colds with zinc: a structured review. Clin Infect Dis 2007;45:569-74. http://dx.doi.org/10.1086/520031

Submitter agrees with default conflict of interest statement:I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.

Contributors

Harri Hemilä

What's new

DateEventDescription
23 March 2012 Amended Typographical errors to feedback comment amended

History

Protocol first published: Issue 1, 1999

Review first published: Issue 2, 1999

DateEventDescription
9 January 2012 Feedback has been incorporated Feedback incorporated
7 September 2011 Amended Authors' replies to Feedback comments added to review.
8 August 2011 Feedback has been incorporated Feedback comments added to review.
17 February 2011 Amended Summary of findings table amended.
29 June 2010 New citation required and conclusions have changed A new team of review authors have updated this previously withdrawn review. In the previous review, the role of zinc for the common cold was inconclusive, as the results could not be pooled due to the paucity of trials measuring clinically relevant outcomes. In this updated review we were able to undertake pooling of results due to the addition of new trials and we found that zinc is beneficial for the common cold.
1 June 2010 New search has been performed Searches conducted. We included eight new trials (Kurugol 2006a; Kurugol 2006b; Kurugol 2007; Macknin 1998; Petrus 1998; Prasad 2000; Prasad 2008; Vakili 2009) and excluded three new trials (McElroy 2003; Turner 2000; Veverka 2009) in this update.
17 June 2008 Amended Converted to new review format
4 May 2006 Amended Review withdrawn
24 February 1999 New search has been performed Review first published Issue 2, 1999

Contributions of authors

Dr Meenu Singh (MS) and Dr Rashmi Ranjan Das (RRD) jointly prepared and edited the review.

Declarations of interest

None known.

Sources of support

Internal sources

  • Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

External sources

  • No sources of support supplied

Notes

There was a change in authorship between the first published version of the review and this updated version. Ian IR Marshall was the review author of both the protocol and review published in The Cochrane Library in 1999. The review was withdrawn and taken over by the current review authors (Meenu Singh and Rashmi Ranjan Das) for updating.

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